Tricyclic triazolobenzazepine derivatives, process for producing the same, and antiallergic agents

ABSTRACT

Tricyclic triazolobenzazepine derivatives in the form of a prodrug are provided. The compounds according to the present invention are those represented by formula (I) and pharmacologically acceptable salts and solvates thereof. The compounds are useful as antiallergic agents and exhibit excellent bioavailability.  
                 
 
     wherein R 1  represents hydrogen, OH, alkyl or phenyl alkyl,  
     R 2 , R 3 , R 4 , and R 5  represent hydrogen, halogen, optionally protected hydroxyl, formyl, optionally substituted alkyl, alkenyl, alkoxy or the like, and  
     Q represents a group selected from the following groups (i) to (iv), halogen, or alkoxy:

BACKGROUND OF THE INVENTION

[0001] 1. Field of the invention

[0002] The present invention relates to a tricyclic triazolobenzazepinederivative having antiallergic activity as a prodrug, an intermediatefor synthesizing the same, a process for producing the same, and anantiallergic agent.

[0003] 2. Background Art

[0004] In recent years, it has been revealed that allergic reactionsinduced by various stimuli such as immunoreactions can be divided intotwo reactions, i.e., an immediate reaction which occurs immediatelyafter the stimulation and a delayed reaction which occurs several hoursafter the stimulation (see, for example, “Laie Asthmatic Responses”, P.M. O'byrne, J. Dolovich and F. E. Hargreave, Am. Rev. Respir. Dis.,1987; 136: 740-751). Especially, the control of the latter reaction hasbecome important.

[0005] Clinical studies show that there are few drugs which aresignificantly effective in inhibiting the delayed allergic reaction.Thus, the development of drugs therapeutically effective in treatingboth the immediate reaction and the delayed reaction has been expectedin the art.

[0006] Sodium cromoglicate has been known as a representative drug forinhibiting the immediate and delayed allergic reactions. This drug isclinically administered by inhalation because it is not useful whenorally administered.

[0007] The administration by inhalation, however, is disadvantageous inthat it is difficult to properly administer the drug to babies, infants,and children and that it is difficult to continuously administer thedrug to patients who are highly sensitive to inhalation stimuli.

[0008] Thus the development of oral drugs which can inhibit both theimmediate and delayed allergic reactions and have excellent efficacyhave been expected in the art.

[0009] In recent years, many studies on antiallergic agents andtherapeutic agents for asthma have been conducted in the art. Tricycliccompounds containing seven membered ring which have been studied includedibenzoxepine derivatives (Japanese Patent Laid-Open Nos. 10784/1988 and78292/1993 and Journal of Chemical & Pharmaceutical Bulletin, vol. 39,No. 10, p. 2724 and p. 2729 (1991)), dibenzoxazepine derivatives(Japanese Patent Laid-Open Nos. 184963/1991, 211071/1992, and 65257/1993and EP 5180720), and dibenzocycloheptene derivatives (WO 93/13068).Further, tricyclic benzazepine derivatives and tricyclic benzothiazepinederivatives are disclosed in EP 0686636, WO 95/18130, and WO 97/00258.

[0010] Meanwhile, a prodrug technique has been known as one means forimproving the bioavailabilitv of a drug (Keiko Toyo Seizai No Sekkei ToHyoka (Design and Assay of Oral Preparation): edited by Mitsuru Hashida,Yakugyo Jiho Co., Ltd., pp. 216-231 (1995)). Chemical modification of acarboxyl, hydroxyl, amino or other group of the drug through an ester,amido, acetal or other bond can improve the bioavailability of the drug.However, any 1,2,3-triazole-modified prodrug has not been reported inthe art.

SUMMARY OF THE INVENTION

[0011] The present inventors have synthesized a tricyclictriazolobenzazepine derivative having a chemically modified triazolering and have found that the derivative has superior bioavailabilitycompared with the corresponding triazolobenzazepine.

[0012] In one aspect of the present invention, there are providedtricyclic triazolobenzazepine derivatives as a prodrug represented byformula (I) and pharmacologically acceptable salts and solvates thereof:

[0013] wherein

[0014] R¹ represents a hydrogen atom, a hydroxyl group, C₁₋₄ alkyl, orphenyl C₁₋₄ alkyl;

[0015] R², R³, R⁴, and R⁵, which may be the same or different, representany one of the following (a) to (n):

[0016] (a) a hydrogen atom;

[0017] (b) a halogen atom;

[0018] (c) an optionally protected hydroxyl group;

[0019] (d) formyl;

[0020] (e) C₁₋₁₂ alkyl which may be substituted by a halogen atom;

[0021] (f) C₂₋₁₂ alkenyl which has one or more carbon-carbon doublebonds and may be substituted by

[0022] (1) a halogen atom,

[0023] (2) cyano,

[0024] (3) —COR⁹ wherein R represents a hydrogen atom or C₁₋₆ alkyl,

[0025] (4) —COOR¹⁰ wherein R¹⁰ represents a hydrogen atom or C₁₋₆ alkyl,

[0026] (5) —CONR¹¹R¹² wherein R¹¹ and R¹², which may be the same ordifferent, represent

[0027] (i) a hydrogen atom,

[0028] (ii) C₁₋₆ alkyl which may be substituted by amino optionallysubstituted by C₁₋₄ alkyl, phenyl optionally substituted by C₁₋₄ alkylwhich may be substituted by a saturated five- to seven-memberedheterocyclic ring containing one or two nitrogen atoms (the nitrogenatoms may be substituted by C₁₋₄ alkyl), or a saturated or unsaturatedfive- to seven-membered heterocyclic ring,

[0029] (iii) phenyl which may be substituted by carboxyl, or

[0030] (iv) a saturated or unsaturated five to seven-memberedheterocyclic ring,

[0031] (6) a saturated or unsaturated five- to seven-memberedheterocyclic ring which may be substituted by C₁₋₄ alkyl or may form abicyclic ring fused with another ring;

[0032] (g) C₁₋₁₂ alkoxy which may be substituted by

[0033] (1) a halogen atom,

[0034] (2) a hydroxyl group,

[0035] (3) cyano,

[0036] (4) C₃₋₇ cycloalkyl,

[0037] (5) phenyl,

[0038] (6) C₁₋₄ alkoxy,

[0039] (7) phenoxy,

[0040] (8) amino which may be substituted by C₁₋₄ alkyl,

[0041] (9) —COR¹³ wherein R¹³ represents a hydrogen atom, C₁₋₆ alkyl,phenyl optionally substituted by a halogen atom or C₁₋₄ alkoxy, orphenyl C₁₋₄ alkyl,

[0042] (10) —COOR¹⁴ wherein R¹⁴ represents a hydrogen atom or C₁₋₆alkyl,

[0043] (11) —CONR¹⁵R¹⁶ wherein R¹⁵ and R¹⁶, which may be the same ordifferent, represent a hydrogen atom or C₁₋₆ alkyl which may besubstituted by a saturated or unsaturated five- to seven-memberedheterocyclic ring, or

[0044] (12) a saturated or unsaturated five- to seven-memberedheterocyclic ring which may be substituted by C₁₋₄ alkyl or phenyl C₁₋₄alkyl;

[0045] (h) —C═N—OR¹⁶ wherein R¹⁶ represents a hydrogen atom, C₁₋₆ alkyl,phenyl C₁₋₄ alkyl, or phenyl;

[0046] (i) —(CH₂)mOR¹⁷ wherein m is an integer of 1 to 4, and R¹⁷represents a hydrogen atom, C₁₋₆ alkyl, or phenyl C₁₋₄ alkyl of whichone or more hydrogen atoms on the benzene ring may be substituted byC₁₋₄ alkyl;

[0047] (j) —(CH₂)k—COR¹⁸ wherein k is an integer of 1 to 4, and R¹⁸represents a hydrogen atom or C₁₋₄ alkyl;

[0048] (k) —(CH₂)j—COOR¹⁹ wherein j is an integer of 0 to 4, and R¹⁹represents a hydrogen atom or C₁₋₆ alkyl;

[0049] (l) —(CH₂)p—NR²⁰R²¹ wherein p is an integer of 1 to 4, and R²⁰and R²¹, which may be the same or different, represent

[0050] (1) a hydrogen atom,

[0051] (2) C₁₋₆ alkyl which may be substituted by amino optionallysubstituted by C₁₋₄ alkyl,

[0052] (3) phenyl C₁₋₄ alkyl,

[0053] (4) —COR²² wherein R²² represents a hydrogen atom or C₁₋₄ alkylwhich may be substituted by carboxyl, or

[0054] (5) —SO₂R²³ wherein R²³ represents C₁₋₄ alkyl or phenyl which maybe substituted by a halogen atom;

[0055] (m) —(CH₂)q—CONR²⁴R²⁵ wherein q is an integer of 0 to 4, and R²⁴and R²⁵, which may be the same or different, represent a hydrogen atom,a saturated or unsaturated five- to seven-membered heterocyclic ring, orC₁₋₆ alkyl which may be substituted by a saturated or unsaturated five-to seven-membered heterocyclic ring, or alternatively R²⁴ and R²⁵ mayform a saturated or unsaturated five- to seven-membered heterocyclicring together with a nitrogen atom to which they are attached (theheterocyclic ring may further contain at least one oxygen, nitrogen, orsulfur atom, may form a bicyclic ring fused with another ring, or may besubstituted by C₁₋₄ alkyl); and

[0056] (n) —NR²⁶R²⁷ wherein R²⁶ and R²⁷, which may be the same ordifferent, represent a hydrogen atom or —COR²⁸ wherein R²⁸ represents ahydrogen atom, C₁₋₆ alkyl, or phenyl which may be substituted by C₁₋₄alkyl or C₁₋₆ alkoxy optionally substituted by phenyl;

[0057] R³¹ and R³², which may be the same or different, represent ahydrogen atom or C₁₋₆ alkyl which may be substituted by a halogen atom;and

[0058] Q represents a group selected from the following groups (i) to(iv) or a halogen atom or C₁₋₆ alkoxy:

[0059] wherein

[0060] R³³ represents

[0061] C₁₋₆ alkyl which may be substituted by C₁₋₆ alkoxy optionallysubstituted by C₁₋₆ alkoxy, phenyl optionally substituted by C₁₋₆alkoxy, amino, or nitro, or a saturated or unsaturated five- toseven-membered heterocyclic ring optionally substituted by C₁₋₆ alkoxy,amino, or nitro,

[0062] phenyl which may be substituted by C₁₋₆ alkoxy, amino, or nitro,or

[0063] a saturated or unsaturated five- to seven-membered heterocyclicring which may be substituted by C₁₋₆ alkoxy, amino, or nitro, or

[0064] R³³ may form C₁₋₄ alkylene together with R³¹ or R³²,

[0065] R³⁴ represents

[0066] C₁₋₁₆ alkyl which may be substituted by a halogen atom, carboxyl,phenyl optionally substituted by C₁₋₆ alkoxy, amino, or nitro, or asaturated or unsaturated five- to seven-membered heterocyclic ringoptionally substituted by C₁₋₆ alkoxy, amino, or nitro,

[0067] phenyl which may be substituted by C₁₋₆, alkoxy, amino, or nitro,or

[0068] a saturated or unsaturated five- to seven-membered heterocyclicring which may be substituted by C₁₋₆ alkoxy, amino, or nitro,

[0069] R³⁵ and R³⁶, which may be the same or different, represent ahydrogen atom or C₁₋₆ alkyl which may be substituted by amino optionallysubstituted by C₁₋₄ alkyl or

[0070] R³⁵ and R³⁶ may form a saturated or unsaturated five- toseven-membered heterocyclic ring together with a nitrogen atom to whichthey are attached, and

[0071] R³⁷ and R³⁸, which may be the same or different, represent C₁₋₆alkyl.

[0072] In another aspect of the present invention, there are providedtricyclic benzazepine derivatives as a prodrug represented by formula(Ia) and pharmacologically acceptable salts and solvates thereof:

[0073] wherein

[0074] R⁴¹ and R⁴², which may be the same or different, represent ahydrogen atom, optionally protected hydroxyl, C₁₋₆ alkoxy which may besubstituted by a halogen atom, or C₁₋₆ alkyl which may be substituted bya halogen atom and

[0075] R³¹, R³², and Q are as defined above.

[0076] The tricyclic triazolobenzazepine derivatives according to thepresent invention are useful for the treatment of allergic diseases.

[0077] In another aspect of the present invention, there is provided apharmaceutical composition comprising as an active ingredient thecompound represented by formula (I) or (Ia) or a pharmacologicallyacceptable salt or a solvate thereof.

[0078] In a further aspect of the present invention, there are providedintermediates for synthesizing the compounds represented by formulae (I)and (Ia).

[0079] Specifically, an intermediate according to the present inventionis a compound represented by formula (II) or a salt or solvate thereof:

[0080] wherein R⁵¹ represents nitro or amino, R⁵² represents a hydrogenatom or a protective group for carboxyl, and Q, R² to R⁵, R³¹, and R³²are as defined above.

[0081] Another intermediate according to the present invention is acompound represented by formula (II′) or a salt or solvate thereof:

[0082] wherein Q, R² to R⁵, R³¹, R³², R⁵¹, and R⁵² are as defined above.

[0083] A further intermediate according to the present invention is acompound represented by formula (VI) or a salt or solvate thereof:

[0084] wherein Q, R² to R⁵, R³¹, R³², and R⁵² are as defined above.

[0085] A further intermediate according to the present invention is acompound represented by formula (VI′) or a salt or solvate thereof:

[0086] wherein Q, R² to R⁵, R³¹, R³², and R⁵² are as defined above.

[0087] A further intermediate according to the present invention is acompound represented by formula (VII) or a salt or solvate thereof:

[0088] wherein R² to R⁵, and R⁵² are as defined above.

[0089] A further intermediate according to the present invention is acompound represented by formula (VIII) or a salt or solvate thereof:

[0090] wherein R⁶¹ represents a protective group for triazole and R² toR⁵, and R⁵² are as defined above.

[0091] A further intermediate according to the present invention is acompound represented by formula (IXa) or a is salt or solvate thereof:

[0092] wherein R⁴¹ to R⁴², and R⁵² are as defined above, provided thatR⁴¹ and/or R⁴² do not represent a hydrogen atom.

[0093] A further intermediate according to the present invention is acompound represented by formula (XVIa) or a salt or solvate thereof:

[0094] wherein R⁴¹ to R⁴², R⁵¹, and R⁵² are as defined above.

[0095] These intermediates are useful in producing the compoundsrepresented by formulae (I) and (Ia).

DETAILED DESCRIPTION OF THE INVENTION

[0096] Definition

[0097] As used herein, the term “alkyl” or “alkoxy” as a group or a partof a group means straight-chain, branched, or cyclic alkyl or alkoxy.

[0098] C₁₋₆ alkyls as used herein include straight-chain alkyls, such asmethyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, branchedalkyls, such as isopropyl, isobutyl, tert-butyl, and 3-pentyl, andcyclic alkyls, such as cvclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

[0099] C₁₋₆ alkoxys as used herein include straight-chain alkoxys having1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy,n-pentyloxy, and n-hexyloxy, branched alkoxys, such as isopropyloxy,isobutyloxy, and tert-butyloxy, and cyclic alkoxys, such ascyclopropyloxy and cyclohexyloxy.

[0100] C₁₋₁₆ alkyls as used herein include, in addition to the aboveC₁₋₆ alkyls, alkyls having 7 to 16 carbon atoms, such as 1-methylhexyl,5-methylhexyl, heptyl, octyl, nonyl, decyl, undecyl, and pentadecyl.

[0101] The term “halogen atom” as used herein means a fluorine,chlorine, bromine, or iodine atom.

[0102] The term “dissimilar atom” as used herein means an oxygen,nitrogen, or sulfur atom.

[0103] The term “saturated or unsaturated five- to seven-memberedheterocyclic ring” as used herein means a heterocycle containing one ormore heteroatoms selected from oxygen, nitrogen, and sulfur atoms.Examples of heterocyclic rings include pyridine, imidazole, oxazole,thiazole, pyrimidine, furan, thiophene, pyrrole, pyrrolidine,piperidine, tetrahydrofuran, and oxazoline.

[0104] Compounds

[0105] In formula (I), R², R³, R⁴, and R⁵ each independently representany one of groups (a) to (n).

[0106] Examples of protective groups for the hydroxyl group (c) includeacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, benzoyl,4-nitrobenzoyl, 3-oxobutyryl, benzyl, diphenylmethyl, triphenylmethyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, methoxymethyl,methoxyethoxymethyl, benzyloxymethyl, trimethylsilyl,tert-butyldimethylsilyl, triphenylsilyl, 2-tetrahydropyranyl, andtrimethylsilylethoxymethoxy.

[0107] (e) C₁₋₁₂ alkyl is preferably C₁₋₆ alkyl, more preferably C₁₋₄alkyl.

[0108] (f) C₂₋₁₂ alkenyl is preferably C₂₋₆, alkenyl, more preferablyC₂₋₄ alkenyl, most preferably vinyl.

[0109] At least one hydrogen atom on the alkenyl may be substituted by(1) a halogen atom, (2) cyano, (3) —COR⁹ (4) —COOR¹⁰, (5) —CONR¹¹R¹², or(6) a saturated or unsaturated five- to seven-membered heterocyclicring.

[0110] In (5) —CONR¹¹R¹², R¹¹ and R¹², which may be the same ordifferent, represent a hydrogen atom or C₁₋₆ alkyl (preferably C₁₋₄alkyl), phenyl, or a saturated or unsaturated five- to seven-memberedheterocyclic ring.

[0111] In this case, this alkyl may be further substituted by amino,phenyl, or a saturated or unsaturated five- to seven-memberedheterocyclic ring.

[0112] Further, one or two hydrogen atoms on this amino may besubstituted by C₁₋₄ alkyl.

[0113] This phenyl may also be substituted by C₁₋₄ alkyl. In this case,this C₁₋₄ alkyl may be substituted by a saturated five- toseven-membered heterocyclic ring containing one or two nitrogen atomsoptionally substituted by C₁₋₄ alkyl. Preferred examples thereof includepiperidino, 4-piperidyl, 1-pyrrolidinyl, piperazinyl, 4-C₁₋₄alkylpiperazinyl, and morpholino.

[0114] (g) C₁₋₁₂ alkoxy is preferably C₁₋₆ alkoxy, more preferably C₁₋₄alkoxy.

[0115] This alkoxy may be substituted by (9) —COR¹³ wherein R¹³represents a hydrogen atom, C₁₋₆ alkyl (preferably C₁₋₄ alkyl), phenyl,or phenyl C₁₋₄ alkyl. In this case, this phenyl may be substituted by ahalogen atom or C₁₋₄ alkoxy. Although the position of the substituent isnot particularly limited, the 2- or 4-position on the phenyl ring ispreferred.

[0116] (g) C₁₋₁₂ alkoxy may be substituted by a saturated or unsaturatedfive- to seven-membered heterocyclic ring as substituent (12). Thisheterocyclic ring is preferably a five- or six-membered heterocyclicsaturated ring containing one or two nitrogen atoms, for example,piperidino, 4-piperidinyl, 1-pyrrolidinyl, piperazinyl, and morpholino.One or more hydrogen atoms on the heterocyclic ring may be furthersubstituted by C₁₋₄ alkyl or phenyl C₁₋₄ alkyl. Preferred examples ofphenyl C₁₋₄ alkyls include benzyls, such as benzyl, 4-methylbenzyl,4-chlorobenzyl, 4-hydroxybenzyl, 4-nitrobenzyl, 4-methoxybenzyl, and4-carboxybenzyl, phenethyl, 3-phenylpropyl, and 4-phenylbutyl.

[0117] In (i) —(CH₂)mOR¹⁷, m is an integer of 1 to 4, preferably aninteger of 1 or 2.

[0118] In (j) —(CH₂)kCOR¹⁸, k is an integer of 0 to 4, preferably 0, 1,or 2.

[0119] In (k) —(CH₂))jCOOR¹⁹, j is an integer of 0 to 4, preferably 0,1, or 2.

[0120] In (m) —(CH₂)qCONR²⁴R²⁵, q is an integer of 0 to 4, preferably 0,1, or 2.

[0121] R²⁴ and R²⁵ may form a saturated or unsaturated five- toseven-membered heterocyclic ring together with a nitrogen atom to whichthey are attached. This heterocyclic ring may further contain one ormore oxygen, nitrogen, or sulfur atoms. The heterocyclic ring may besubstituted by C₁₋₄ alkyl. Preferred examples of heterocyclic ringinclude piperazino, piperidino, N-methylpiperazino, morpholino,succinimide, indolyl, 4-methylindolyl, 5-methylindolyl, isoindolyl,phthalimido, 4-methylphthalimido, and 1,1-dioxo-2-benzothiazolyl.

[0122] In formulae (I) and (Ia), Q may represent a halogen atom, C₁₋₆alkoxy (preferably C₁₋₄ alkoxy), or any one of groups (i) to (iv).

[0123] In group (i), one or more hydrogen atoms on this C₁₋₆ alkylrepresented by R³³ may be substituted by C₁₋₆ alkoxy, phenyl, or asaturated or unsaturated five- to seven-membered heterocyclic ring(preferably a six-membered heterocycle containing one hetero atom).Further, one or more hydrogen atoms on this C₁₋₆ alkoxy may besubstituted by C₁₋₆ alkoxy. One or more hydrogen atoms on this phenyland the heterocyclic ring may be substituted by C₁₋₆ alkoxy, amino, ornitro.

[0124] Preferred examples of C₁₋₆ alkyls represented by R³³ includemethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl,isobutyl, tert-butyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1,3-diethoxy-2-propyl, 2-isopropoxyethyl, phenethyl,3-pyridylmethyl, 4-methoxyphenethyl, and 2-(2-methoxyethoxy)ethoxy.

[0125] R³³ may represent phenyl. This phenyl may be substituted by C₁₋₆alkoxy, amino, or nitro, preferably nitro. Preferred examples of phenylsrepresented by R³² include 4-nitrophenyl.

[0126] Further, R³³ may represent a saturated or unsaturated five- toseven-membered heterocyclic ring (preferably a six-membered heterocyclecontaining one hetero atom). At least one hydrogen atom on theheterocyclic ring may be substituted by C₁₋₆ alkoxy, amino, or nitro,preferably nitro. Preferred examples of saturated or unsaturated five-to seven-membered heterocyclic ring represented by R³³ include4-piperazyl, 4-piperidyl, and 4-tetrahydropyranyl.

[0127] Further, R³³ may form C₁₋₄ alkylene together with any one of R³¹and R³². Preferred examples of C₁₋₄ alkylenes include methylene. WhenR³³ forms methylene together with R³¹ or R³² and R³¹ or R³² which is notbonded to R³³ represents a hydrogen atom, then —CQR³¹R³² represents4-(2-oxo)-1,3-dioxolyl.

[0128] In group (ii), one or more hydrogen atoms on C₁₋₁₆ alkylrepresented by R³⁴ may be substituted by a halogen atom, carboxyl,phenyl, or a saturated or unsaturated five- to seven-memberedheterocyclic ring (preferably a six-membered heterocyclic ringcontaining one hetero atom). Further, one or more hydrogen atoms on thephenyl and the heterocycle may be substituted by C₁₋₆ alkoxy, amino, ornitro.

[0129] Preferred examples of C₁₋₁₆ alkyls represented by R³⁴ includemethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl,isobutyl, tert-butyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1-methylhexyl, 5-methylhexyl, heptyl, octyl, nonyl, decyl,undecyl, pentadecyl, chloromethyl, 3-chloropropyl, 2-carboxyethyl,morpholinomethyl, 4-methoxybenzyl, and 4-piperazinylmethyl.

[0130] R³⁴ may represent phenyl. The phenyl may be substituted by C₁₋₆alkoxy, amino, or nitro, preferably amino. Preferred examples of phenylsrepresented by R³⁴ include 4-aminophenyl.

[0131] Further, R³⁴ may represent a saturated or unsaturated five- toseven-membered heterocyclic ring (preferably a six-membered heterocyclicring containing one hetero atom). One or more hydrogen atoms on theheterocyclic ring may be substituted by C₁₋₆ alkoxy, amino, or nitro,preferably amino. Preferred examples of saturated or unsaturated five-to seven-membered heterocyclic rings represented by R³, include3-pyridyl and 4-pyridyl.

[0132] In group (iii), one or more hydrogen atoms on C₁₋₆ alkylrepresented by R³⁵ and R³⁶ may be substituted by amino. Preferredexamples of C₁₋₆ alkyls represented by R³⁵ and R³⁶ include2-(N,N-dimethylamino)ethyl. Preferred examples of saturated orunsaturated five- to seven-membered heterocyclic rings formed bycombining R³⁵ with R³⁶ include 1-morpholino, 1-imidazolyl, and4-piperazinyl.

[0133] A group of preferred compounds represented by formula (I)include:

[0134] a group of compounds wherein R¹, R², R³, R⁴, and R⁵ represent ahydrogen atom or (g) C₁₋₁₂ alkoxy (preferably C₁₋₆ alkoxy) and Qrepresents group (i) (preferably R²³ represents C₁₋₄ alkyl optionallysubstituted by C₁₋₄ alkoxy);

[0135] a group of compounds wherein R¹ represents a hydrogen atom, R²,R³, R⁴, and R⁵ represent a hydrogen atom or (g) C₁₋₁₂ alkoxy (preferablyC₁₋₁₆ alkoxy), and Q represents group (i) (preferably, R³³ representsC₁₋₄ alkyl optionally substituted by C₁₋₄ alkoxy);

[0136] a group of compounds wherein R¹, R², and R⁵ represents a hydrogenatom, R³ and R⁴ represent a hydrogen atom or (g) C₁₋₁₂ alkoxy(preferably C₁₋₆ alkoxy), and Q represents group (i) (preferably, R³³represents C₁₋₄ alkyl optionally substituted by C₁₋₄ alkoxy);

[0137] a group of compounds wherein R¹, R², and R⁵ represent a hydrogenatom, R³ and R⁴ represent a hydrogen atom or (f) C₂₋₁₂ alkenyl, and Qrepresents group (i) (preferably, R³³ represents C₁₋₄ alkyl optionallysubstituted by C₁₋₄ alkoxy);

[0138] a group of compounds wherein R¹, R², and R⁵ represent a hydrogenatom, R³ and R⁴ represent a hydrogen atom or (e) C₁₋₁₂ alkyl, and Qrepresents group (i) (preferably, R³³ represents C₁₋₄ alkyl optionallysubstituted by C₁₋₄ alkoxy);

[0139] a group of compounds wherein R¹, R², and R⁵ represent a hydrogenatom, R³ and R⁴ represent a hydrogen atom, or (j) group —(CH₂)kCOR¹⁸,(l) —(CH₂)pNR²⁰R²¹, (m) —(CH₂)qCONR²²R²³ or (n) —NR²⁹R³⁰, Q representsgroup (i) (preferably, R³³ represents C₁₋₄ alkyl optionally substitutedby C₁₋₄ alkoxy);

[0140] a group of compounds wherein R¹, R², R⁴, and R⁵ represent ahydrogen atom, R³ represents (g) C₁₋₁₂ alkoxy (preferably C₁₋₆ alkoxy),and Q represents group (i) (preferably, R³³ represents C₁₋₄ alkyloptionally substituted by C₁₋₄ alkoxy); and

[0141] a group of compounds wherein R¹, R², R³, and R⁵ represent ahydrogen atom, R⁴ represents (g) C₁₋₁₂ alkoxy (preferably, C₁₋₆ alkoxy),and Q represents group (i) (preferably, R³³ represents C₁₋₄ alkyloptionally substituted by C₁₋₄ alkoxy).

[0142] In formulae (I) and (Ia), —CR³¹R³²Q is preferably located at the2-position in the triazole ring.

[0143] One or more hydrogen atoms on C₁₋₆ alkyl represented by R³¹ andR³² in formulae (I) and (Ia) and one or more hydrogen atoms on the C₁₋₆alkyl and the C₁₋₆ alkoxy in its alkyl portion represented by R⁴¹ andR⁴² in formula (Ia) may be substituted by a halogen atom. Examples ofthe substituted alkyls and alkyl portions include trifluoromethyl,2-fluoroethyl, difluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl,2-chloroethyl, dichloromethyl, 2,2,2-trichloroethyl, tribromomethyl,2-bromoethyl, dibromomethyl, 2,2,2-tribromoethyl, pentafluoroethyl,fluoromethyl, 3,3,3-trifluoropropyl, 4,4,4-trichlorobutyl,5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0144] Protective groups for optionally protected hydroxyl which may berepresented by R⁴¹ and R⁴² include acetyl, chloroacetyl, dichloroacetyl,trichloroacetyl, benzoyl, 4-nitrobenzoyl, 3-oxobutyryl, benzyl,diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, trimethylsilyl,tert-butyldimethylsilyl, triphenylsilyl, 2-tetrahydropyranyl, andtrimethylsilylethoxymethoxy.

[0145] R⁴¹ and R⁴² represent preferably C₁₋₄ alkoxy, more preferablymethoxy or isopropyl. Still more preferably, R⁴¹ represents methoxy, andR⁴² represents methoxy or isopropyl.

[0146] A group of preferred compounds represented by formula (Ia)include a group of compounds wherein R⁴¹ and R⁴² represent C₁₋₆ alkoxy(preferably C₁₋₄ alkoxy, more preferably methoxy or isopropyl), and Qrepresents group (i) (preferably, R³³ represents optionally C₁₋₄alkoxy-substituted C₁₋₄ alkyl).

[0147] Among the compounds according to the present invention,particularly preferred compounds include

[0148] 2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benz azepine,

[0149]2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-tria zolo[4,5-c][1]benzazepine,

[0150]2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-8-isopropoxy-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine, and

[0151]8-isopropoxy-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo [4,5-c][1]benzazepine.

[0152] In the present invention, protective groups for carboxylrepresented by R⁵² include, for example, methyl, ethyl, tert-butyl,benzyl, 4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl,tert-butyldimethylsilyl, triphenylsilyl, 2-phenylsulfonylethyl,2-methoxycarbonylethyl, 2-cyanoethyl, and 2-trimethylsilylethyl.

[0153] In the present invention, “protective groups for triazole”represented by R⁶¹ include, for example, benzyl optionally substitutedby a halogen atom, hydroxyl, nitro, C₁₋₆ alkyl, or C₁₋₆ alkoxy,diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,3,4,5-trimethoxybenzyl, trimethylsilyl, tert-butyldimethylsilyl,methoxymethyl, benzyloxymethyl, and methoxyethoxy.

[0154] A group of preferred intermediate compounds represented byformulae (II), (II′), (VI), and (VI′) include compounds wherein R² andR⁵ represent a hydrogen atom, R³ and R⁴ each independently represent ahydrogen atom, optionally protected hydroxyl, optionally substitutedC₁₋₆ alkoxy, optionally substituted C₁₋₆ alkyl (preferably, optionallysubstituted C₁₋₆ alkoxy), and Q represents group (i) (preferably, R³³represents C₁₋₄ alkyl optionally substituted by C₁₋₄ alkoxy).

[0155] A group of preferred intermediate compounds represented byformulae (VII) and (VIII) include compounds wherein R² and R⁵ representa hydrogen atom and R³ and R⁴ each independently represent a hydrogenatom, optionally protected hydroxyl, optionally substituted C₁₋₆ alkoxy,and optionally substituted C₁₋₆ alkyl (preferably, optionallysubstituted C₁₋₆ alkoxy)

[0156] Preferred examples of compounds represented by formulae (VI) and(VI′) include

[0157] ethyl5-(3,4-dimethoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate,

[0158] ethyl2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5-(3-isopropoxy-4-methoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate,

[0159] ethyl5-(3,4-dimethoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxy)carbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate,and

[0160] ethyl2-(1-(1,3-diethoxy-2-propoxy)carbonyloxy-2-methylpropyl)-5-(3-isopropoxy-4-methoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate.

[0161] Examples of preferred compounds represented by formula (VII)include.

[0162] methyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate,

[0163] ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate,

[0164] methyl5-(3-isopropoxy-4-methoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate, and

[0165] ethyl5-(3-isopropoxy-4-methoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate.

[0166] Examples of preferred compounds represented by formula (IX)include

[0167] methyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate,

[0168] ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate, methyl4-(3-isopropoxy-4-methoxyphenyl)-4-oxo-2-butynoate, and

[0169] ethyl 4-(3-isopropoxy-4-methoxyphenyl)-4-oxo-2-butynoate.

[0170] Examples of preferred compounds represented by formula (XVI)include ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butynoate andethyl 4-(5-isopropoxy-4-methoxy -2-nitrophenyl)-4-oxo-2-butynoate.

[0171] In the compounds according to the present invention, tautomersand position isomers derived from triazole ring, cis-trans isomersderived from alkenyl as the substituent, and enantiomers derived fromthe group —CQR³³R³⁴ may exist, and any of the isomers and a mixturethereof fall within the scope of the present invention.

[0172] The compounds according to the present invention may be formedinto pharmacologically acceptable salts thereof. Such salts includenon-toxic salts. Preferred salts include alkali metal or alkaline earthmetal salts, such as sodium, potassium, and calcium salts,hydrohalogenic acid salts, such as hydrofluoride salts, hydrochloridesalts, hydrobromide salts, and hydroiodide salts, inorganic acid salts,such as nitric acid salts, perchloric acid salts, sulfuric acid salts,and phosphoric acid salts, lower alkylsulfonic acid salts, such asmethanesulfonic acid salts, trifluoromethanesulfonic acid salts, andethanesulfonic acid salts, arylsulfonic acid salts, such asbenzenesulfonic acid salts and p-toluenesulfonic acid salts, organicacid salts, such as fumaric acid salts, succinic acid salts, citric acidsalts, tartaric acid salts, oxalic acid salts, and maleic acid salts,and amino acid salts, such as glutamic acid salts and aspartic acidsalts.

[0173] Solvates of the compounds according to the present inventioninclude hydrates and ethanol solvates.

[0174] Production of Compounds

[0175] The compounds according to the present invention may besynthesized by the following process 1 or 2.

[0176] <Process 1>

[0177] The compound represented by formula (I) may be produced byreacting a compound represented by formula (III)

[0178] wherein R¹ to R⁵ are as defined above, with a compoundrepresented by formula (IV)

[0179] wherein Q, R³¹, and R³² are as defined above and Hal represents ahalogen atom,

[0180] in a solvent which is not involved in the reaction (for example,water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropyl ether,methylene chloride, acetone, N,N-dimethylformamide, dimethylsulfoxide)in the presence of a base at a temperature of 0 to 150° C. for 1 to 48hr. Bases as used herein, include organic bases such as pyridine andtriethylamine, and inorganic bases such as potassium carbonate, sodiumcarbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydroxide,and potassium hydroxide. Preferably, the compound may be prepared by thereaction in N,N-dimethylformamide in the presence of sodiumhydrogencarbonate at a reaction temperature of 20 to 100° C. for 1 to 24hr. The compound represented by formula (I) is produced as a mixture ofa 1-substituted triazole, a 2-substituted triazole, and a 3-substitutedtriazole in any ratio.

[0181] The compound represented by formula (III) may be produced byprocesses described, for example, in WO 95/18130 and WO 97/00258.

[0182] The compound represented by formula (I) may be purified byconventional purification methods, for example, recrystallization,reprecipitation, solvent extraction, column chromatography on silicagel, or column chromatography on adsorptive resin.

[0183] <Process 2>

[0184] The compound represented by formula (I) may be produced byreducing the compound of formula (IIa)

[0185] wherein Q, R² to R⁵, R³¹, R³², and R⁵² are as defined above, toprepare a compound represented by formula (IIb)

[0186] wherein Q, R² to R⁵, R³¹, and R⁵² are as defined above, and thencyclizing the compound represented by formula (IIb).

[0187] Conventional catalytic reductions (preferably in the presence ofa nickel or palladium catalyst in a solvent, for example, ethyl acetate,an alcohol solvent such as ethanol, water, or a mixture thereof) orreduction using a metal such as iron or zinc, for example, reduction ina zinc-acetic acid system, and the like may be used for the reductionreaction. The reduction may be carried out at a temperature of 10 to100° C. for 0.1 to 10 hr.

[0188] The cyclization may be carried out by reacting the compoundrepresented by formula (IIb) with a strong base such as sodium hydride,potassium hydride, sodium methoxide, sodium ethoxide, or potassiumtert-butoxide, in a solvent which is not involved in the reaction (forexample, an alcohol such as methanol, ethanol, or isopropyl alcohol,toluene, N,N-dimethylformamide, dimethylsulfoxide, dioxane,tetrahydrofuran, or a mixture of two or more of these solvents) at atemperature of 0 to 100° C. for 1 to 48 hr, generally 5 to 24 hr.

[0189] The cyclization reaction may also be carried out in an aceticacid or trifluoroacetic acid solvent by reacting the compoundrepresented by formula (IIb) at a temperature of 20 to 100° C. for 1 to24 hr.

[0190] After the cyclization, Q may be further converted to anothersubstituent.

[0191] In both the above reduction and cyclization reactions, theposition isomerization of the substituent on the triazole is notobserved. When a compound represented by formula (IIa′) is used alone,the compound represented by formula (I) is obtained as a singlecompound.

[0192] The compound represented by formula (I) may be purified byconventional purification methods, for example, recrystallization,reprecipitation, solvent extraction, column chromatography on silicagel, or column chromatography on adsorptive resin.

[0193] The compound represented by formula (IIa) may be synthesizedaccording to the following scheme. In the scheme, M represents lithium,magnesium chloride, magnesium bromide, magnesium iodide, zinc bromide,zinc iodide, cadmium bromide, cadmium iodide, or copper, R-representssodium, C₁₋₆ alkylsilyl (for example, trimethylsilyl), or C₁₋₆ alkyltin,and Q, Hal, R⁻ to R⁵, R³¹, R³², R⁵², and R³¹ are as described above.

[0194] Synthesis (1) of Compound of Formula (IIa)

[0195] The compound represented by formula (IIa) may be produced from acompound represented by formula (V) by the following process A, B, C orD. According to the process B, C, or D, the compound represented byformula (IIa) having the substituent —CQR³¹R³² (represented by formula(IIa′)) can be prepared, wherein the substituent is introduced into thetriazole ring at its 2-position.

[0196] <Process A>

[0197] The compound represented by formula (IIa) may be prepared byreacting the compound represented by formula (V):

[0198] wherein Q, R² to R⁵, and R⁵² are as defined above, with thecompound represented by formula (IV) according to process 1. As with thecompound (I) prepared by process 1, the compound represented by formula(IIa) thus prepared is a mixture of three types of isomers. For example,the compound represented by formula (V) may be prepared in accordancewith a process described in WO 95/18130.

[0199] <Process B>

[0200] wherein Q, R² to R⁵, R³¹, R³², and R⁵² are as defined above.

[0201] The compound represented by formula (V) is reacted with a ketoneor an aldehyde represented by R³¹R³²C═O in a solvent which is notinvolved in the reaction (for example, methylene chloride, ethylacetate, or acetonitrile) at a temperature of −78 to 100° C., preferably−20 to 50° C. for 0.1 to 24 hr, generally 0.1 to 1 hr. In this case, ahemiacetal represented by the compound (V′) is produced in the reactionsystem. This reaction is promoted by the addition of an acid catalyst.Preferred acid catalysts used herein include protonic acids such asp-toluenesulfonic acid, pyridinium salt of p-toluenesulfonic acid,D-(+)-camphorsulfonic acid, trifluoroacetic acid, sulfuric acid,hydrochloric acid, perchloric acid and phosphoric acid, and Lewis acids,such as boron trifluoride-diethyl ether complex, aluminum chloride, andtitanium tetrachloride.

[0202] Q in formula (IIa′) may be introduced by further adding variousreactants to the compound represented by formula (V′). The compoundrepresented by formula (IIa′) wherein Q is any one of groups (i) to(iv), a halogen atom, or a C₁₋₆ alkoxy may be synthesized in accordancewith the following.

[0203] (1) The compound represented by formula (IIa′) wherein Q is group(1) may be prepared by reacting the reaction solution containing thecompound represented by formula (V′) with a compound represented byformula R⁷¹—C(═O)—R⁷² (wherein R⁷¹ and R⁷² each independently representa chlorine atom, 4-nitrophenyl, or 1-imidazolyl) including1,1′-carbonyldiimidazole, phosgene, p-nitrophenyl chloroformate, orbis(p-nitrophenyl) carbonate, optionally in the presence of a base suchas pyridine, to prepare a compound represented by formula (IIa′) whereinQ represents —OCOR⁷¹ (wherein R⁷¹ represents a chlorine atom,4-nitrophenyl, or 1-imidazolyl) and then reacting the resulting compoundwith an alcohol represented by formula R³³OH (wherein R³³ is as definedabove). The substituent Q may be further converted to anothersubstituent.

[0204] (2) The compound represented by formula (IIa′) wherein Qrepresents group (ii) may be prepared by adding an acylating agentrepresented by R³⁴COHal (wherein Hal and R³⁴ are as defined above) or(R³⁴CO)₂O (wherein R is as defined above) to the reaction solutioncontaining the compound represented by formula (V′), optionally in thepresence of a base such as pyridine.

[0205] The compound represented by formula (IIa′) wherein Q representsgroup (ii) may also be prepared by fusing the compound represented byformula (V′) with a compound represented by formula R³⁴ COOH (whereinR³⁴ is as defined above). Preferred condensing agents used hereininclude active esterifying agents such as dicyclohexylcarbodiimide,pyridine derivatives, and phosphoric acid derivatives, and dehydratingagents such as thionyl chloride and phosphorus oxychloride.

[0206] The compound may also be prepared by reacting the compound (IIa′)(wherein the substituent Q represents a halogen atom, which may besynthesized by a process described in process (4), with a sodium orpotassium salt of a carboxylic acid represented by formula R³⁴COOH(wherein R³⁴ is as defined above) in a solvent which is not involved inthe reaction in the presence of tetra-n-butylammonium bromide. Q may befurther converted to another substituent.

[0207] (3) The compound represented by formula (IIa′) wherein Qrepresents group (iii) may be prepared by reacting the compound,produced in process (1) represented by formula (IIa′) (wherein R² to R⁵,R³¹, R³², and R⁵² are as defined above and Q represents —OCOR⁷¹ (whereinR⁷¹ is as defined above)), optionally after isolation, with an aminerepresented by R³⁵R³⁶NH (wherein R³⁵ and R³⁶ are as defined above).

[0208] (4) The compound represented by formula (IIa′), wherein Qrepresents group (iv), a halogen atom, or C₁₋₆ alkoxy, may be preparedby adding a chlorophosphoric ester represented by (R³⁷O)(R³⁸O)POCl, analcohol represented by R⁷³OH (wherein R⁷³ represents C₁₋₆ alkyl), or ahalogenating agent such as thionyl chloride or thionyl bromide, to thereaction solution containing the compound (V′). The reaction may becarried out generally at a temperature of −20 to 100° C. for 0.1 to 48hr.

[0209] All the compounds represented by formula (IIa′) synthesized bythe process via the hemiacetal represented by the compound (V′) areobtained as triazoles substituted at the 2-position.

[0210] <Process C>

[0211] The compound represented by formula (IIa′), wherein Q representsgroup (i), may be prepared by reacting the compound represented byformula (V) with a compound represented by R³¹R³²C═O (wherein R³¹ andR³² are as defined above) (for example, isobutyl aldehyde) in an organicsolvent such as acetone, acetonitrile, or ethyl acetate, at atemperature of −20 to 100° C., preferably 22 to 28° C., to prepare acompound represented by formula (V′) and then reacting the compoundrepresented by formula (V′) in the same solution with a compoundrepresented by HalCOOR³³ (wherein Hal and R³² are as defined above) (forexample, isopropyl chlorocarbonate), together with an alkali metalcarbonate such as sodium carbonate or potassium carbonate, and an alkalimetal iodide such as sodium iodide or potassium iodide, at 25 to 60° C.,post-treating the product, and crystallizing the treated product.Solvents used for the crystallization include lower alcohols, such asmethanol, ethanol, and isopropyl alcohol. These solvents may be usedtogether with water.

[0212] All the compounds represented by formula (IIa′) synthesized bythis process are obtained as triazoles substituted at the 2-position.The above process is advantageous in that 1,1′-carbonyldiimidazole,which is expensive and unstable, is not used as the reactant, anyby-product derived from 1,1′-carbonyldiimidazole is not produced, andthe compounds represented by formula (IIa′) wherein Q represents thegroup (i) are obtained in high purity at high yield.

[0213] <Process D>

[0214] The compound represented by formula (IIa′), wherein Q representsgroup (i), may also be prepared by directly reacting the compoundrepresented by formula (V) with the compound represented by formula (IV)(for example, 1-chloro-2-methylpropyl-isopropyl carbonate).

[0215] More specifically, the compound represented by formula (V) may bereacted with the compound represented by formula (IV) in an organicsolvent such as acetone, acetonitrile, ethyl acetate, orN,N-dimethylformamide, together with an inorganic base such as sodiumcarbonate, potassium carbonate, cesium carbonate, or sodium hydroxide,and an alkali metal iodide such as sodium iodide or potassium iodide, at25 to 60° C. for 1 to 70 hr.

[0216] The compound represented by formula (IIa′) may be purified byconventional purification methods, for example, a solvent extraction,crystallization, or column chromatography on silica gel.

[0217] All the compounds represented by formula (IIa′) synthesized bythe above process can be advantageously obtained as triazolessubstituted at the 2-position. This seems to be due to the addition ofthe alkali metal iodide to the reaction system. The process is furtheradvantageous in that the compounds represented by formula (IIa′) can besimply produced from the compound represented by formula (V) in a singlestep. An additional advantage of the process is that the formation ofby-products derived from impurities contained in a ketone or an aldehyde(for example, isobutyric acid in isobutylaldehyde) represented byR³¹R³²C═O which is reacted with the compound represented by formula (V)in the process B and C can be avoided and high-purity compoundsrepresented by formula (IIa′) can be obtained.

[0218] Synthesis (2) of Compound of Formula (IIa)

[0219] The compound represented by formula (IIa) may be produced bynitration of the compound represented by formula (VI). The nitration maybe carried out in the presence of a nitrating agent such as(concentrated) nitric acid or fuming nitric acid without a solvent or ina solvent which is not involved in the reaction (for example, aceticanhydride, concentrated sulfuric acid, methylene chloride, orchloroform) at −10 to 50° C. for 10 min to 24 hr.

[0220] The compound represented by formula (VI) may be prepared byintroducing —CQR³¹R³² into the triazole group of the compoundrepresented by formula (VII). The substituent —CQR³¹R³² may beintroduced according to the process A, B, C, or D.

[0221] The compound represented by formula (VII) may be prepared bydeprotecting the compound represented by formula (VIII).

[0222] The deprotection may be carried out according to a methoddescribed in D. R. Buckle and C. J. M. Rockell, J. Chem. Soc., PerkinTrans. I, 627 (1982), F. E. Nielsen, E. B. Pedersen, J. Heterocycl.Chem., 22, 1693 (1985) Specifically, when R⁶¹ represents a benzyl,diphenylmethyl, triphenylmethyl, 4-methoxybenzyl,3,4,5-trimethoxybenzyl, benzyloxymethyl, or trimethylsilyl, thedeprotection may be carried out by reacting the compound represented byformula (VIII) with a mineral acid such as dilute hydrochloric acid ordilute sulfuric acid, or an organic acid such as trifluoroacetic acideither as such or after dilution with a solvent which is not involved inthe reaction (for example, methylene chloride or toluene) at 15 to 80°C. for 1 to 24 hr.

[0223] The compound represented by formula (VII) may also be prepared byreacting the compound represented by formula (XII) with the compoundrepresented by formula (XIII′) in a solvent which is not involved in thereaction (for example, tetrahydrofuran, diethyl ether, diisopropylether, tert-butyl methyl ether, or toluene) at −78 to 100° C. for 15 minto 24 hr. The compound represented by formula (XIII′) may be easilyproduced by reacting metal azide compounds such as sodium aziderepresented by formula (x′), various alkylsilyl azides, and variousalkyltin azides, with an acetylenedicarboxylic diester.

[0224] The compound represented by formula (VII) may also be prepared byreacting the compound represented by formula (IX) with the metal azidecompound represented by formula (XI) in a solvent which is not involvedin the reaction (for example, water, ethanol, isopropyl alcohol,tetrahydrofuran, diisopropyl ether, methylene chloride, acetone,toluene, ethyl acetate, N,N-dimethylformamide, or dimethylsulfoxide) at0 to 120° C. for 1 to 24 hr.

[0225] Synthesis of Compound Represented by Formula (VIII)

[0226] The compound represented by formula (VIII) may be prepared byreacting the compound represented by formula (IX) with the azide organiccompound represented by formula (X) such as p-methoxybenzyl azide. Thereaction may be carried out by a reaction of the compound represented byformula (IX) with the compound represented by formula (X′).

[0227] The compound represented by formula (IX) may be prepared byreacting the compound represented by formula (XI) with chlorine,bromine, or iodine in a solvent which is not involved in the reaction(for example, water, ethanol, isopropyl alcohol, tetrahydrofuran,diisopropyl ether, methylene chloride, acetic acid,N,N-dimethylformamide, or dimethylsulfoxide) at −10 to 30° C. for 10 minto 24 hr and then reacting the resultant halide with an organic basesuch as triethylamine, diisopropylethylamine, triisopropylamine,pyridine, picoline, lutidine, collidine, or quinoline, or an inorganicbase such as potassium carbonate sodium carbonate, cesium carbonate,potassium hydrogencarbonate, or sodium hydrogencarbonate in the absenceof a solvent or in a solvent which is not involved in the reaction (forexample, water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropylether, methylene chloride, acetone, toluene, N,N-dimethylformamide, ordimethylsulfoxide) at 0 to 50° C. for 1 to 24 hr.

[0228] The compound represented by formula (XI) may be prepared by amethod described, for example, in Eur. J. Med. Chem., 23, 45 (1988) orU.S. Pat. No. 4,562,068.

[0229] The compound represented by formula (VIII) may also be preparedby converting a halo benzene represented by formula (XIV) to anorganometal compound represented by formula (XII) (for example, Mrepresents lithium, magnesium chloride, magnesium bromide, magnesiumiodide, zinc bromide, zinc iodide, cadmium bromide, cadmium iodide,copper or the like) and then reacting the compound represented byformula (XII) with the compound represented by formula (XIII) in asolvent which is not involved in the reaction (for example,tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methylether, or toluene) at −78 to 100° C. for 15 min to 24 hr. The compoundrepresented by formula (XIII) may be easily prepared by reacting anazide compound (X) synthesized, for example, by a method described in J.Heterocyclic Chem., 21, 1669 (1984) with an acetylenedicarboxylicdiester.

[0230] Synthesis of Compound of Formula (V)

[0231] The compound represented by formula (V) may be prepared bydeprotecting the compound represented by formula (XV). The deprotectionmay be carried out by the method described in connection with thedeprotection of the compound represented by formula (VIII) to producethe compound represented by formula (VII).

[0232] The compound represented by formula (V) may also be produced byreacting the compound represented by formula (XVI) with the compoundrepresented by formula (X′). The reaction may be carried out by themethod described above in connection with the reaction of the compoundrepresented by formula (IX) with the compound represented by formula(X′).

[0233] The compound represented by formula (V) may also be produced bynitrating the compound represented by formula (VII). The nitration maybe carried out by the method described above in connection with thenitration of the compound represented by formula (VI) to produce thecompound represented by formula (IIa).

[0234] The compound represented by formula (XV) may be produced byreacting the compound represented by formula (XVI) with the compoundrepresented by formula (X). The reaction may be carried out by themethod described above in connection with the reaction of the compoundrepresented by formula (IX) with the compound represented by formula(X).

[0235] The compound represented by formula (XVI) may be produced fromthe compound represented by formula (XVII) by the method described abovein connection with the production of the compound represented by formula(IX) from the compound represented by formula (XI).

[0236] The compound represented by formula (XVII) may be produced by amethod described, for example, in Eur. J. Med. Chem., 23, 45 (1988) orU.S. Pat. No. 4,562,068.

[0237] The compound represented by formula (XV) may also be produced bynitrating the compound represented by formula (VIII). The nitration maybe carried out by the method described above in connection with thenitration of the compound represented by formula (VI) to produce thecompound represented by formula (IIa).

[0238] Further, the compound represented by formula (XV) may also beproduced, for example, by a method described in Wo 95/18130.

[0239] Pharmaceutical Composition

[0240] Oral administration of the compound represented by formula (I)according to the present invention to experimental animals have shownthat the compound represented by formula (III) is detected in a higherconcentration in plasma compared with administration of the compoundrepresented by formula (III) alone. WO 95/18130 and WO 97/00258 discloseuse of the compound represented by formula (III) as a therapeutic agentfor allergic diseases. The compound represented by formula (I), after itis passed through various mucous membranes including digestive tracts,is converted in vivo to the compound represented by formula (III) whichdevelops antiallergic activity.

[0241] The compound according to the present invention can be used astherapeutic agents for allergic diseases, for example, bronchial asthma,aczema, hives, allergic gastroenteritis, allergic rhinitis, and allergicconjunctivitis. The term “therapy” or “treatment” include “prevention”or “prophylaxis.” When orally administered, the compound according tothe present invention may be formulated using conventionalpharmaceutically acceptable excipients (for example, lactose,crystalline cellulose, starch, and calcium phosphate), binders (forexample, starch, sodium carmellose, and hydroxypropylcellulose),disintegrators (calcium carmellose, calcium carbonate and the like), andlubricants (magnesium stearate, talc and the like) into tablets,capsules, granules, dry syrups, and various liquid preparations commonlyused in medical treatment by conventional methods. Further, thesevarious preparations may also be sustained—release preparations whichrelease the ingredient for a long period of time.

[0242] According to pharmacological activities including antiallergicaction of the compound represented by formula (III), the compoundaccording to the present invention may be applied to various treatmentsthrough administration routes other than oral administration. Dosageforms for this purpose include, but are not limited to, sublingualtablets, suppositories, inhalants, nasal drops, eye drops, andpercutaneous absorption preparations, for example, patches orointments/creams.

[0243] Although the content of the compound according to the presentinvention in the pharmaceutical composition depends on the preparations,it is generally in the range of from 1 to 70% by weight, preferably fromabout 5 to 50% by weight, based on the whole composition.

[0244] The dose for the treatment of allergic diseases may beappropriately determined individually in view of the direction for use,the age and sex of patients, the severity of symptoms and the like. Inthe case of oral preparations, sublingual tablets, or suppositories,however, the compound according to the present invention, or the salt orsolvate thereof may be administered at a dose in the range of from 0.05to 5 g/day, preferably 0.1 to 1.0 g/day, at one time or dividedlyseveral times. Regarding other dosage forms, the dose may be properlyincreased or decreased depending on the intended use.

EXAMPLES

[0245] The present invention is further illustrated by the followingExamples that are not intended as a limitation of the invention.

Synthesis Example 1

[0246] 7,8-Dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine

[0247] (a) 1.5 N butyl lithium (26.8 ml, 40.2 mmol) was added to asolution of diisopropylamine (6.0 ml, 42.8 mmol) in tetrahydrofuran (75ml) under an argon atmosphere at −78° C. The mixture was stirred for onehr. Ethyl propiolate (3.4 ml, 33.5 mmol) and a solution of4,5-dimethoxy-2-nitrobenzaldehyde (5.0 g, 23.7 mmol) in tetrahydrofuran(50 ml) were added thereto in that order, and the mixture was stirred at−78° C. for additional 1.5 hr. A solution of acetic acid (7.0 ml, 122mmol) in tetrahydrofuran (20 ml) was added thereto, followed by additionof water. The mixture was extracted with ethyl acetate. The organiclayer was washed with dilute hydrochloric acid, water, a saturatedaqueous sodium hydrogencarbonate solution, and saturated brine solutionin that order. The organic layer was then dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to give ethyl4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butynoate as an oil (8.59 g)The resultant ethyl4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butynoate was dissolved intoluene (80 ml).

[0248] 4-Methoxybenzyl azide (11.6 g, 71.1 mmol) was added to thesolution. The mixture was heated at 100° C. with stirring overnight. Thereaction solution was cooled to room temperature and then purified bycolumn chromatography on silica gel (hexane:ethyl acetate=2:1).

[0249] The precipitate created in the eluate was collected by filtrationto give a 1:5 mixture (2.60 g, 23%) of ethyl4-(hydroxy-(4,5-dimethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)) and ethyl5-(hydroxy-(4,5-dimethoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate(a-2: high polar product (MP)). On the other hand, the filtrate wasconcentrated under reduced pressure to give a 2.5:1 mixture (4.68 g,42%) of the compound (a-1: (LP)) and the compound (a-2: (MP))

[0250] 2.5:1 Mixture of a-1 (LP) and a-2 (MP)

[0251]¹H-NMR (CDCl₃): δ 1.38 (15/7H, t), 1.39 (6/7H, t), 3.56 (6/7H, s),3.72 (6/7H, s), 3.78 (15/7H, s), 3.91 (6/7H, s), 3.97 (15/7H, s), 3.99(15/7H, s), 4.41 (4/7H, q), 4.44 (10/7H, q), 4.97 (5/7H, d), 5.07 (2/7H,d), 5.48 (2/7H, d), 5.78 (5/7H, d), 5.71 (2/7H, d), 5.84 (5/7H, d), 6.32(2/7H, s), 6.83 (10/7H, d), 6.67 (4/7H, d), 6.99 (4/7H, d), 7.07 (2/7H,d), 7.21 (10/7H, d), 7.48 (2/7H, s), 7.51 (5/7H, s), 7.71 (5/7H, s).

[0252] EIMS: m/z 472 (M⁺)

[0253] (b) Manganese dioxide (14 g) was added to a solution of the 2.5:1mixture (4.63 g, 9.80 mmol) of the compound a-1 and the compound a-2prepared in step (a) in methylene chloride (100 ml). The mixture wasstirred at room temperature overnight. Manganese dioxide (4.6 g) wasadded thereto, and the mixture was stirred at room temperature for 8 hr.The reaction solution was filtered through Celite, followed by washingwith ethyl acetate. The solvent was evaporated under reduced pressure.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1) to give ethyl1-(4-methoxybenzyl)-4-(4,S-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylateas a brown crystal powder (b-1: LP) (2.75 g, 60%) and ethyl1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylateas a brown crystal powder (b-2: MP) (1.12 g, 24%).

[0254] b-1(LP):

[0255]¹H-NMR (CDC₃): δ 1.38 (3H, t), 3.78 (3H, s), 3.98 (3H, s), 4.02(3H, s), 4.43 (2H, q), 5.72 (2H, s), 6.85 (2H, d), 6.99 (1H, s), 7.24(2H, d), 7.69 (1H, s).

[0256] SIMS: m/z 471 (M⁺+1)

[0257] b-2 (MP):

[0258]¹H-NMR (CDCl₃): δ 1.19 (3H, t), 3.79 (3H, s), 3.91 (3H, s), 4.00(3H, s), 4.10 (2H, q), 5.79 (2H, s), 6.80 (1H, s), 6.88 (2H, d), 7.42(2H, d), 7.52 (1H, s)

[0259] EIMS: m/z 470 (M⁺).

[0260] (c) A 1 N aqueous sodium hydroxide solution (13 ml) was added toa solution of ethyl1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate(b-1) (3.04 g, 6.46 mmol), prepared in step (b), in tetrahydrofuran (40ml). The mixture was stirred at room temperature for 3.5 hr. Thereaction solution was diluted with ether, and water was added thereto.The aqueous layer was acidified with hydrochloric acid and extractedwith ethyl acetate, followed by washing with water and saturated brinesolution. The organic layer was dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure to give1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxyicacid as light yellow oil (c-1′: LP) (2.55 g, 89%). The resultant1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylicacid (c-1′:LP) (1.07 g, 2.42 mmol) was dissolved in a mixed solventcomposed of ethanol (50 ml) and ethyl acetate (50 ml). 10%palladium-carbon (129 mg) was added thereto. The mixture was stirred ina hydrogen atmosphere at room temperature for 4 hr. Methylene chloridewas added to the reaction solution to dissolve the precipitated crystal,followed by filtration through Celite. The filtrate was concentratedunder reduced pressure to give4-(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylic acid (c-1: LP) (1.06 g, 100%-).

[0261] c-1′ (LP);

[0262]¹H-NMR (CDCl₃): δ 3.78 (3H, s), 3.99 (3H, s), 4.06 (3H, s), 6.02(2H, s), 6.84 (2H, d), 6.94 (1H, s), 7.40 (2H, d), 7.76 (1H, s), 13.80(1H, brs).

[0263] SIMS: m/z 443 (M⁺+1).

[0264] c-1 (LP);

[0265]¹H-NMR (CDCl₃): δ 3.78 (3H, s), 3.88 (3H, s), 3.94 (3H, s), 6.06(2H, s), 6.11 (1H, s), 6.86 (2H, d), 7.45 (2H, d), 8.58 (1H, s).

[0266] SIMS: m/z 413 (M⁺+1).

[0267] Likewise, ethyl1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(b-2) (3.12 g, 6.63 mmol) prepared in step (b) was hydrolyzed in atetrahydrofuran (100 ml) solution with a 1 N aqueous sodium hydroxidesolution (13 ml) at room temperature for 3.5 hr. Thus,1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylicacid (c-2′: MP) (2.32 g, 79%) was obtained as a yellow crystal powder.

[0268] c-2′ (MP);

[0269]¹H-NMR (CDCl₃): δ 3.80 (3H, s), 3.94 (3H, s), 4.00 (3H, s), 5.79(2H, s), 6.89 (1H, s), 6.91 (2H, d), 7.47 (2H, d), 7.54 (1H, s).

[0270] SIMS: m/z 443 (M⁺+1).

[0271] (d) Tributylamine (0.64 ml, 2.69 mmol),2-fluoro-1′methylpyridinium p-toluenesulfonate (793 mg, 2.80 mmol), and3,4-dihydro-2H-pyrido[1, 2-a]pyrimidin-2-one (453 mg, 3.06 mmol) wereadded in that order to a solution of4-(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylicacid (c-1) (1.05 g, 2.55 mmol) in methylene chloride (30 ml) in an argonatmosphere under ice cooling. The mixture was stirred under ice coolingfor one hr and then stirred at room temperature for 2 hr.

[0272] Water was added to the reaction mixture, and the mixture wasextracted with chloroform. The organic layer was washed with dilutehydrochloric acid, water, saturated aqueous sodium hydrogencarbonatesolution, and saturated brine solution. The organic layer was dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The resultant precipitate was collected by filtration, washedwith diethyl ether and water, and dried to give7,8-dimethoxy-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo[4,5-c][1]benzazepine as light yellow crystalpowder (d-1: LP) (477 mg, 48%).

[0273] d-1 (LP):

[0274]¹H-NMR (DMSO-d₆): δ 3.72 (3H, s), 3.84 (6H, s), 6.09 (2H, s), 6.90(2H, d), 7.16 (1H, s), 7.30 (2H, d), 7.67 (1H, s), 11.33 (1H, s).

[0275] EIMS: m/z 394 (M⁺)

[0276] (e) Anisole (0.5 ml) and trifluoroacetic acid (5.0 ml) were addedto 7,8-dimethoxy-3-(4-methoxybenzyl)-4(5H),10-dioxo-3H-1,2,3-triazolo[4,5-c][l]benzazepine (d-1) (471 mg, 1.19mmol). The mixture was stirred at 60° C. for 3 hr. Thereafter, thesolvent was evaporated under reduced pressure. The resultant precipitatewas collected by filtration, washed with diethyl ether and water, andthen dried to give the title compound 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine (e) as yellow powder(319 mg, 98%). The 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c] [1]benzazepine (e) (238 mg, 0.867mmol) was dissolved in a 1 N aqueous sodium hydroxide solution. Thesolution was purified on Diaion HP-20 (water:acetone=9:1) to give thetitle compound: a sodium salt of 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine (e′) as light yellowpowder (231 mg, 90%).

[0277] e:

[0278]¹H-NMR (DMSO-d₆): δ 3.85 (3H, s), 3.86 (3H, s), 7.22 (1H, s), 7.70(1H, s), 11.23 (1H, s).

[0279] SIMS: m/Z 275 (M⁺+1).

[0280] e′:

[0281] FDMS: m/z 274 (M⁺—Na+1)

Synthesis Example 2

[0282] Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,23-triazole-4-carboxylate

[0283] Anisole (1 ml) was added to a solution of an about 1:1 mixture(4.4 g) of ethyl1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate(Synthesis Example 1, b-1) and ethyl1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(SynthesisExample 1, b-2) in trifluoroacetic acid (10 ml), and the mixture wasstirred at 60° C. for 10 hr. After the mixture was allowed to stand forcooling, the solvent was evaporated under reduced pressure, followed byazeotropic evaporation using toluene. The resultant crystal wascollected by filtration, washed with diethyl ether, and then dried togive ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (3.12 g, 95%).

[0284]¹H-NMR (CDCl₃): δ 1.42 (3H, t), 4.00 (3H, s), 4.03 (3H, s), 4.47(2H, q), 7.02 (1H, s), 7.67 (1H, s).

Synthesis Example 3

[0285] Ethyl4-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylateand ethyl5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate

[0286] (a) 1.5 N butyl lithium (22.6 ml, 33.8 mmol) was added to asolution of diisopropylamine (5.0 ml, 36.0 mmol) in tetrahydrofuran (75ml) under an argon atmosphere at −78° C., and the mixture was stirredfor one hr. Ethyl propiolate (2.9 ml, 28.2 mmol) and a solution ofS-isopropoxy-4-methoxy-2-nitrobenzaldehyde (4.5g, 18.8 mmol) intetrahydrofuran (50 ml) were then added thereto in that order, and themixture was stirred at −78° C. for additional 1.5 hr. A solution ofacetic acid (5.9 ml, 102 mmol) in tetrahydrofuran (20 ml) was added tothe reaction solution. Water was then added thereto, followed byextraction with ethyl acetate. The organic layer was washed with dilutehydrochloric acid, water, a saturated aqueous sodium hydrogencarbonatesolution, and saturated brine solution. The organic layer was dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give ethyl4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate (7.27 g).The resultant ethyl4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate wasdissolved in toluene (60 ml). 4-Methoxybenzyl azide (9.2 g, 56.4 mmol)was added to the solution. The mixture was heated at 100° C. withstirring overnight. The reaction solution was cooled to roomtemperature. The solvent was evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=1:2) to give a 1:1 mixture (7.01 g, 75-O) of ethyl4-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate(a-1: low polar product (LP)) and ethyl5-(l-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2;3-triazole-4-carboxylate(a-2: high polar product (MP))

[0287] 1:1 mixture of a-1 (LP), a-2 (MP):

[0288]¹H-NMR (CDCl₃): δ 1.34-1.55 (9H, m), 3.59 (1H, d), 3.77 (3H, s),3.92 (3H, s), 4.41 (2H, q), 4.69-4.76 (1H, m), 5.81 (1H, s), 5.83 (1H,s), 6.82 (2H, d), 6.93 (1H, d), 7.20 (2H, d), 7.43 (1H, s), 7.67 (1H,s).

[0289] SIMS: m/z 501 (M⁺+1).

[0290] (b) Active manganese dioxide (24 g) was added to a solution ofthe 1:1 mixture (7.01 g, 14.02 mmol) of the compound (a-1) and thecompound (a-2), prepared in the above step (a), in methylene chloride(160 ml), and the mixture was stirred at room temperature overnight. Thereaction solution was filtered through Celite and washed with methylenechloride. The solvent was then evaporated under reduced pressure to givea 1:1 mixture (6.98 g, 100%) of ethyl4-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate(b-1: LP) and ethyl5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate(b-2: MP) as a foam.

[0291] 1:1 Mixture of b-1 (LP), b-2 (MP):

[0292]¹H-NMR (CDCl₃): δ 1.17 (3/2H, t), 1.37-1.43 (9/2H, m), 3.78 (3H,s), 3.97 (3/2H, s), 3.99 (3/2H, s), 4.08 (1H, q), 4.42 (1H, q),4.55-4.60 (1/2H, m), 4.67-4.72 (1/2H, m), 5.70 (1H, s), 5.78 (1H, s),6.79 (1/2H, s), 6.84-6.88 (2H, m), 6.97 (1/2H, s), 7.24 (1H, d), 7.42(1H, d), 7.52 (1/2H, s), 7.67 (1/2H, s).

[0293] EIMS: m/z 498 (M⁺)

[0294] Intermediate 1 Methyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate

[0295] A solution of bromine (0.05 ml) in methylene chloride (5 ml) wasadded dropwise to a solution of methyl4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (201 mg, 0.8 mmol) inmethylene chloride (5 ml) under ice cooling over a period of 20 min. Themixture was stirred under ice cooling for 1 hr. The reaction temperaturewas then raised to room temperature. The reaction solution was treatedby a conventional method to give methyl2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate (332 mg, 100%) in theform of a diastereo mixture (mixing ratio=61:39) as a colorless foam.The diastereo mixture was used in the next reaction without separation.

[0296] Major component: ¹H-NMR (CDCl₃): δ 3.74 (3H, s), 3.92 (3H, s),3.95 (3H, s), 4.83 (1H, d), 5.44 (1H, d), 6.91 (1H, d), 7.49 (1H, d),7.64 (1H, dd)

[0297] EIMS: m/z 411 (M⁺+1).

[0298] Minor component: ¹H-NMR (CDCl₃): δ 3.88 (3H, s), 3.94 (3H, s),3.96 (3H, s), 4.96 (1H, d), 5.62 (1H, d), 6.92 (1H, d), 7 .57 (1H, d),7.64 (1H, dd)

[0299] EIMS: m/z 411 (M⁺+1).

[0300] A solution of triethylamine (27 mg) in methylene chloride (0.5ml) was added to a solution of methyl2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate (49 mg, 0.1 mmol),prepared above, in methylene chloride (0.5 ml). The mixture was stirredat room temperature for 15 min and then heated under reflux withstirring for 2 hr. The mixture was then treated by a conventionalmethod, and the crude product was purified by column chromatography onsilica gel (hexane/ethyl acetate) to give the title compound as a yellowcrystal (21 mg, 71%).

[0301]¹H-NMR (CDCl₃): δ 3.89 (3H, s), 3.95 (3H, s), 3.99 (3H, s), 6.94(1H, d), 7.56 (1H, d), 7.82 (1H, dd).

[0302] EIMS: m/z 248 (M⁺).

[0303] Intermediate 2 Ethyl 4-(3,4-Dimethoxyphenyl)-4-oxo-2-butynoate

[0304] The procedure as described above in connection with Intermediate1 was repeated to prepare ethyl2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate (7.3 g, 95%) in theform of a diastereo mixture as a colorless foam (mixing ratio=63:37)from a solution of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (4.8g, 18 mmol) in methylene chloride (500 ml) and a solution of bromine(1.1 ml) in methylene chloride (100 ml). The diastereo mixture was usedin the next reaction without separation.

[0305] Major component: ¹H-NMR (CDCl₃): δ 1.24 (3H, t), 3.94 (3H, s),3.97 (3H, s), 4.20 (2H, q), 4.84 (1H, d), 5.46 (1H, d), 6.93 (1H, d),7.51 (1H, d), 7.66 (1H, dd)

[0306] EIMS: m/z 424 (M⁺)

[0307] Minor component: ¹H-NMR (CDCl₃): δ 1.38 (3H, t), 3.96 (3H, s),3.98 (3H, s), 4.36 (1H, q), 4.97 (1H, d), 5.65 (1H, d), 6.94 (1H, d),7.59 (1H, d), 7.67 (1H, dd)

[0308] EIMS: m/z 424 (M⁺+1).

[0309] A solution of ethyl2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate (4.76 g, 11.2 mmol),prepared above, in methylene chloride (20 ml) and a solution oftriethylamine (4 g) in methylene chloride (5 ml) were subjected toreaction and treatment in the same manner as described above inconnection with Intermediate 1. The crude product was purified by columnchromatography on silica gel (hexane/ethyl acetate) to give the titlecompound (2.4 g, 82%) as a yellow crystal.

[0310]¹H-NMR (CDCl₃): δ 1.37 (3H, t), 3.94 (3H, s), 3.98 (3H, s), 4.35(2H, q), 6.95 (1H, d), 7.57 (1H, d), 7.83 (1H, dd).

[0311] EIMS: m/z 262 (M⁺)

[0312] Intermediate 3 Ethyl4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butynoate

[0313] The procedure as described above in connection with Intermediate1 was repeated to prepare ethyl2,3-dibromo-4-(4,5-dimethoxy-2-nitrophenyl)-4-oxobutanoate (337 mg,100%) in the form of a diastereo mixture as light brown oil (mixingratio−2:1) from a solution of ethyl4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butenoate (199 mg, 0.6 mmol) inmethylene chloride (10 ml) and a solution of bromine (0.04 ml) inmethylene chloride (5 ml). The diastereo mixture was used in the nextreaction without separation.

[0314] Major component: ¹H-NMR (CDCl₃): δ 1.32 (3H, t), 4.01 (6H, s),4.31 (2H, q), 5.03 (1H, d), 5.52 (1H, d), 6.99 (1H, s), 7.63 (1H, s).

[0315] Minor component: ¹H-NMR (CDCl₃): δ 1.34 (3H, t), 4.01 (6H, s),4.31 (2H, q), 4.91 (1H, d), 5.25 (1H, d), 7.02 (1H, s), 7.65 (1H, s).

[0316] Diisopropylethylamine (74 μl) was allowed to act on the product(90 mg, 0.2 mmol), prepared above, in methylene chloride (1 ml). Thecrude product was purified by column chromatography on silica gel(hexane/ethyl acetate) to give the title compound (17 mg, 29%) as ayellow crystal powder.

[0317] This compound may also be produced by oxidizing ethyl4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butynoate described inSynthesis Example 1 in methylene chloride with active manganese dioxideunder conventional reaction conditions (for example, at room temperaturefor 10 hr).

[0318]¹H-NMR (CDCl₃): δ 1.36 (3H, t), 4.01 (3H, s), 4.02 (3H, s), 4.27(2H, q), 7.06 (1H, s), 7.55 (1H, s).

[0319] Intermediate 4 Methyl5-(3,4-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylateand methyl 4-(3,4-dimethoxybenzoyl)-3-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate

[0320] A solution of 4-methoxybenzyl azide (37 mg, 0.2 mmol) in toluene(1 ml) was added to a solution of methyl4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate (47 mg, 0.2 mmol)(Intermediate 1) in toluene (1 ml). The mixture was stirred at 100° C.for 18 hr. The reaction solution was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate) to give the title compound (low polarcolorless oil (30 mg, 39%) and high polar compound as a light yellowfoam (40 mg, 51%)).

[0321] Low Polar Compound:

[0322]¹H-NMR (CDCl₃): δ 3.71 (3H, s), 3.72 (3H, s), 3.87 (3H, s), 3.88(3H, s), 5.75 (2H, s), 6.80 (2H, d), 6.82 (1H, d), 7.26 (2H, d), 7.58(1H, dd), 7.62 (1H, d).

[0323] EIMS: m/z 411 (M⁺)

[0324] High Polar Compound:

[0325]¹H-NMR (CDCl₃): δ 3.60 (3H, s), 3.64 (3H, s), 3.81 (3H, s), 3.85(3H, s), 5.43 (2H, s), 6.57 (2H, d), 6.60 (1H, d), 6.77 (1H, d), 6.99(2H, d), 7.25 (1H, d).

[0326] EIMS: m/z 412 (M⁺+1).

[0327] Intermediate 5 Ethyl5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate

[0328] In the same manner as in Intermediate 4, a solution of4-methoxybenzyl azide (1.8 g) in toluene (10 ml) was added to a solutionof ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate (intermediate 2) (2.4g, 9.2 mmol) in toluene (80 ml). The mixture was stirred at 100° C. for18 hr. The reaction solution was concentrated under reduced pressure togive a mixture of ethyl5-(3,4-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylateand ethyl4-(3,4-dimethoxybenzoyl)-3-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylateas an oil. The oil was used in the next reaction without purification.

[0329] Major component: ¹H-NMR (CDCl₃): δ 1.08 (3H, t) 3.68 (3H, s),3.88 (3H, s), 3.92 (3H, s), 4.18 (2H, q), 5.51 (2H, s), 6.64 (2H, d),6.67 (1H, d), 6.86 (2H, d), 77.07 (1H, dd), 7.31 (!H, d)

[0330] Minor component: ¹H-NMR (CDCl₃): δ 1.14 (3H, t), 3.80 (3H, s),3.94 (3H, s), 3.95 (3H, s), 4.24 (2H, q), 5.82 (2H, s), 6.85-6.90 (3H,m), 7.33 (2H, d), 7.63 (1H, dd), 7.68 (1H, d).

[0331] A mixture of the above crude product, trlfluoroacetic acid (7.9ml), and anisole (1.2 g) was heated with stirring at 90° C. for 2 hr.The reaction mixture was concentrated under reduced pressure. Ethylacetate was added to the residue. The mixture was extracted with asaturated aqueous sodium hydrogencarbonate solution. The aqueous layerwas neutralized with hydrochloric acid and again extracted with ethylacetate. The organic layer was washed with brine solution and dried overanhydrous magnesium sulfate. The solvent was evaporated to give thetitle compound as a light yellow solid (2.9 g, 91% in two steps).

[0332]¹H-NMR (CDCl₃): δ 1.23 (3H, s), 3.95 (3H, s), 3.96 (3H, s), 4.31(2H, q), 5.59 (2H, s), 6.87 (1H, d), 7.41 (1H, dd), 7.62 (1H, d)

[0333] Intermediate 6 Ethyl 5(or4)-(3,4-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4 (or5)-carboxylate

[0334] (a) A solution of butyl lithium in hexane (1.58 M, 0.24 ml, 0.39mmol) was added at −78° C. to a solution of 4-bromoveratrol (50 μl, 0.35mmol) in tetrahydrofuran (1.5 ml) under an argon atmosphere. After 15min, this solution was added at −78° C. to a solution of diethyl1-(4-methoxybenzyl)-1H-1,2,3-triazole-4, 5-dicarboxylate (117 mg, 0.35mmol) in tetrahydrofuran (1 ml). The mixture was stirred for 40 min. Asaturated aqueous ammonium chloride solution was added to the reactionsolution. The mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine solution and dried. The solventwas evaporated. The residue was purified by column chromatography onsilica gel (ethyl acetate/hexane) to give the title compound as a singlecompound (60 mg, 40%). The Rf value of silica gel thin-layerchromatography on silica gel and ¹H-NMR spectrum were the same as thosefor the major component of the mixture of two position isomers obtainedby the conversion of Intermediate 5 to a triazole compound.

[0335]¹H-NMR (CDCl₃): δ 1.08 (3H, t), 3.68 (3H, s), 3.88 (3H, s), 3.92(3H, s), 4.18 (2H, q), 5.51 (2H, s), 6.64 (2H, d), 6.67 (1H, d), 6.86(2H, d), 7.07 (1H, dd), 7.31 (1H, d).

[0336] EIMS: m/z 425 (M⁺)

[0337] (b) A solution of 4-bromoveratrol (183 mg, 0.84 mmol) intetrahydrofuran (1 ml) was added to a mixture of magnesium (33 mg, 1.36mg atom) in tetrahydrofuran (1 ml) at room temperature under an argonatmosphere. After 20 min, the reaction solution was heated under refluxfor 30 min. A minor amount of iodine was added thereto, followed bystirring for additional 20 min. The reaction solution was added to asolution of diethyl1-(4-methoxybenzyl)-1H-1,2,3-triazole-4,5-dicarboxylate (218 mg, 0.84mmol) in tetrahydrofuran (1 ml) under ice cooling. The temperature ofthe reaction solution was raised, and the reaction solution was thenstirred at room temperature for 3 days. A saturated aqueous ammoniumchloride solution was added to the reaction solution to stop thereaction. The reaction mixture was treated in the same manner as in step(a) and purified by column chromatography on silica gel to give thetitle compound (68 mg, 19%0).

[0338] Intermediate 7 Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylateand ethyl4-(4,5-dimethoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate

[0339] In the same manner as in Intermediate 4,4-methoxybenzyl azide (19mg) was added to a solution of ethyl4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butynoate (17 mg, 0.055 mmol),synthesized as described above in connection with Intermediate 3, intoluene (1 ml). The mixture was stirred at 60° C. for 20 hr. Thereaction solution was concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate) to give yellowcrystal powder (low polar product: high polar product=2:3 mixture) (19mg, 73%). The Rf value of thin-layer chromatography on silica gel and¹H-NMR (CDCl₃) spectrum were the same as those for compounds b-1 (highpolar product) and b-2 (low polar product) prepared in Synthesis Example1.

[0340] Intermediate 8 Ethyl5-(3,4-dimethoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate

[0341] p-Toluenesulfonic acid monohydrate (482 mg, 2.5 mmol) andisobutylaldehyde (3.4 ml, 37 mmol) were added to a solution of ethyl5-(3,4-dimethoxybenzoyl)-1H-1,2,3-tria zole-4-carboxylate (7.7 g, 25mmol), prepared in the same manner as described above in connection withIntermediate 5, in methylene chloride (115 ml) under an argon atmosphereat −20° C. The mixture was stirred at −20° C. for one hr.Carbonyldiimidazole (6.2 g, 38 mmol) was added thereto, followed bystirred at −20° C. for additional one hr. Isopropyl alcohol (20 ml) wasadded thereto. The mixture was cooled to −30° C. Trifluoroacetic acid(5.8 ml, 75 mmol) was added thereto. The mixture was stirred at roomtemperature for 18 hr. The reaction solution was treated by aconventional method and purified by column chromatography on silica gel(hexane/ethyl acetate) to give the title compound as a colorless liquid(10.9 g, 93.4%).

[0342]¹H-NMR (CDCl₃): δ 0.87 (3H, d), 1.15 (3H, d), 1.27 (3H, t), 1.28(3H, d), 1.33 (3H, d), 2.76 (1H, m), 3.94 (3H, s), 3.96 (3H, s), 4.34(2H, q), 4.90 (1H, sept), 6.54 (1H, d), 6.89 (1H, d), 7.47 (1H, d), 7.64(IH, s)

[0343] TSPMS: m/z 464 (M⁺+1).

[0344] Intermediate 9 Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate

[0345] 70% nitric acid (1 ml) was added to ethyl5-(3,4-dimethoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate(86 mg, 0.19 mmol) as Intermediate 8 under ice cooling. The mixture wasstirred at that temperature for 30 min. The reaction solution was pouredinto ice and then extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous sodium hydrogencarbonate solution andsaturated brine solution in that order and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give the title compoundas a single compound (49 mg, 52%). The Rf value of thin-layerchromatography on silica gel and ¹H-NMR spectrum were the same as thoseof the title compound of Example 20 (a).

[0346]¹H-NMR (CDCl₃): δ 0.72 (3H, d), 1.05 (3H, d), 1.25 (3H, d), 1.28(3H, d), 1.44 (3H, t), 2.56 (1H, m), 4.00 (3H, s), 4.08 (3H, s), 4.49(2H, q), 4.85 (1H, m), 6.35 (1H, d), 7.06 (1H, s), 7.62 (1H, s).

Example 1

[0347] 1-(1-Isopropoxycarbonyloxyethyl)-7-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine (substituted at1-position), 2-(1-isopropoxycarbonyloxyethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benz azepine (substituted at2-position), and 3-(1-isopropoxycarbonyloxyethyl)-7,8-dimethoxy-4(5H)10-dioxo-3H-1,2,3-triazolo[4,5-c][1]benzazepine (substituted at3-position)

[0348] 1-Iodoethylisopropyl carbonate (2.82 g) and sodiumhydrogencarbonate (919 mg) were added to a solution of7,8-dimethoxy-4(5H), 10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine(Synthesis Example 1) (1.00 g) in N,N-dimethylformamide (20 ml) under anargon atmosphere. The mixture was stirred at 60° C. for 18 hr. Thesolvent was evaporated under reduced pressure. Water and ethyl acetatewere added thereto. The organic layer was separated. The organic layerwas washed with water and saturated brine solution in that order anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The resultant mixture was repeatedly purified bycolumn chromatography on silica gel (hexane/ethyl acetate). As a result,the compound substituted at 3-position (275 mg), the compoundsubstituted at 2-position (55 mg), and the compound substituted at1-position (66 mg) were obtained each as yellow powder in the order ofelution.

[0349] 1-(1-Isopropoxycarbonyloxyethyl)-7,8-dimethoxy-4 (5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine (substituted at1-position)

[0350]¹H-NMR (CDCl₃): δ 1.24 (3H, d), 1.29 (3H, d), 2.14 (1H, d), 3.98(3H, s), 4.08 (3H, s), 4.80-4. 90 (2H, m), 7.10 (1H, s), 7.74 (1H, s),7.80 (1H, q), 11.07 (1H, s).

[0351] 2-1-Isopropoxycarbonyloxyethyl)-7,8-dimethoxy-4 (5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine (substituted at2-position)

[0352]¹H-NMR (CDCl₃): δ 1.27 (3H, d), 1.31 (3H, d), 2.06 (1H, d), 4.00(3H, s), 4.06 (3H, s), 4.85-4.95 (2H, m), 6.85 (1H, s), 7.13 (1H, q),787 (1H, s), 9.97 (1H, s).

[0353] 3-(1-Isopropoxycarbonyloxyethyl)-7,8-dimethoxy-4 (5H),10-dioxo-3H-1,2,3-triazolo[4,5-c][1]benzazepine (compound substituted at3-position)

[0354]¹H-NMR (CDCl₃) δ 1.21 (3H, d), 1.29 (3H, d), 2.12 (1H, d), 4.00(3H, s), 4.01 (3H, s), 4.75-4.85 (2H, m), 6.57 (1H, s), 7.90 (1H, s),7.91 (1H, q), 8.86 (1H, s).

Example 2

[0355] 7,8-Dimethoxy-4 (5H),10-dioxo-1-(pivaloyloxymethyl)-1H-1,2,3-triazolo[4,5-c][1]benzazepine(substituted at 1-position), 7,8-dimethoxy-4(5H),10-dioxo-2-(pivaloyloxyme thyl)-2H-1,2,3-triazolo[4,5-c][1]benzazepine(substituted at 2-oosition) and 7,8-dimethoxv-4 (SH) 10-dioxo-3-(pivaloyloxymethyl)-3H-1,2,3-triazolo[4,5-c][1]benzazepine (substituted at3-position)

[0356] The title compound (345 mg, 89%) was prepared as a mixture ofthree compounds from 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine (Synthesis Example 1)(296 mg) in the same manner as in Example 1, except thatpivaloyloxymethyl chloride and sodium iodide were used instead of1-iodoethylisopropyl carbonate. This was purified by columnchromatography on silica gel (hexane/ethyl acetate) to separate threeisomers as yellow powders.

[0357] 7,8-Dimethoxy-4 (5H),10-dioxo-1-(pivaloyloxymethyl)-1H-1,2,3-triazolo[4,5-c][1]benzazepine(substituted at 1-position)

[0358]¹H-NMR (DMSO-d₆) δ 1.13 (9H, s), 3.85 (6H, s), 6.74 (2H, s), 7.18(1H, s), 7.70 (1H, s), 11.48 (1H, s). 7, 8-Dimethoxy-4 (5H),10-dioxo-2-(pivaloyloxymethyl)-2H-1,2,3-triazolo[4,5-c][1]benzazepine(substituted at 2-position)

[0359]¹H-NMR (DMSO-d₆): δ 1.16 (9H, s), 3.84 (3H, s), 3.85 (3H, s), 6.54(2H, s), 7.17 (1H, s), 7.64 (1H, s), 11.17 (1H, s).

[0360] 7,8-Dimethoxy-4(5H),10-dioxo-3-(pivaloyloxymethyl)-3H-1,2,3-triazolo[4,5-c][1]benzazepine(substituted at 3-position)

[0361]¹H-NMR (DMSO-d₆) δ 1.12 (9H, s), 3.83 (3H, s), 3.86 (3H, s), 6.70(2H, s), 7.20 (1H, s), 7.59 (1H, s), 11.29 (1H, s).

Example 3

[0362] 2-(Ethoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0363] (3a) Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (70 mg) and p-toluenesulfonic acid monohydrate (17mg) were suspended in methylene chloride (10 ml) under an argonatmosphere. Paraformaldehyde (6 mg) was added thereto. The mixture wasstirred at room temperature for 30 min. Pyridine (0.05 ml) and ethylchloroformate (0.04 ml) were added thereto, and the mixture was stirredat room temperature for one hr. Further, pyridine (0.02 ml) and ethylchloroformate (0.04 ml) were added thereto, and the mixture was stirredfor 10 min. The solvent was evaporated under reduced pressure. Ethylacetate (15 ml) and a saturated aqueous sodium hydrogencarbonatesolution (10 ml) were added thereto, followed by separation. The organiclayer was washed with a saturated aqueous sodium hydrogencarbonatesolution (10 ml) and saturated brine solution (10 ml) in that order anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give ethyl2-(ethoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylateas a light yellow foam (48 mg, 53%).

[0364]¹H-NMR (CDCl₃): δ 1.31 (3H, t), 1.44 (3H, t), 4.01 (3H, s), 4.03(3H, s), 4.25 (2H, q), 4.49 (2H, q), 6.21 (2H, s), 7.02 (1H, s), 7.66(1H, s).

[0365] EIMS: m/z 452 (M⁺).

[0366] (3b) Ethyl2-(ethoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(45 mg) prepared in step (3a) was dissolved in ethyl acetate (1 ml).Palladium hydroxide (15 mg) was added to the solution. The mixture wasstirred in a hydrogen atmosphere at room temperature for 15 hr. Thereaction solution was filtered through Celite. The filtrate wasconcentrated under reduced pressure to give ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylateas a yellow oil (40 mg, 95%).

[0367]¹H-NMR (CDCl₃): δ 1.27 (3H, t), 1.33 (3H, t), 3.66 (3H, s), 3.90(3H, s), 4.27 (2H, q), 4.34 (2H, q), 6.15 (1H, s), 6.38 (2H, s), 6.49(2H, brs), 6.76 (1H, s).

[0368] EIMS: m/z 422 (M⁺).

[0369] (3c) Ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(40 mg) prepared in step (3b) was dissolved in acetic acid (2 ml). Thesolution was stirred at 100° C. for 2 hr. After the solution was allowedto cool, the solvent was evaporated under reduced pressure. Water wasadded to the residue. The resultant precipitate was collected byfiltration, washed with saturated aqueous sodium hydrogencarbonatesolution and water, and dried to give the title compound as a yellowcrystal powder (20 mg, 56%).

[0370]¹H-NMR (DMSO-d₆): δ 1.23 (3H, t), 3.84 (3H, s), 3.86 (3H, s), 4.22(2H, q), 6.56 (2H, s), 7.18 (1H, s), 7.65 (1H, s), 11.2 (1H, brs)

[0371] EIMS: m/z 376 (M⁺)

Example 4

[0372] 2-(Isobutoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1 2,3-triazolo[4,5-c][1]benzazepine

[0373] (4a) In the same manner as in Example 3 (3a), provided thatisobutyl chloroformate was used instead of ethyl chloroformate, ethyl2-(isobutoxycarbonyloxymethyl)-5-(4, 5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-car boxylate (172 mg, 90%) was prepared as a light yellowoil from ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (Synthesis Example 2) (140 mg).

[0374]¹H-NMR (CDCl₃): δ 0.92-0.96 (6H, m), 1.44 (3H, t), 1.93-2.04 (1H,m), 3.90-3.98 (2H, m), 4.00 (3H, s), 4.03 (3H, s), 4.50 (2H, q), 6.21(2H, s), 7.01 (1H, s), 7.65 (1H, s).

[0375] EIMS: m/z 480 (M⁺).

[0376] (4b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isobutoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(148 mg, 94%) was prepared as a yellowish brown oil from ethyl2-(isobutoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(170 mg) prepared in step (4a).

[0377]¹H-NMR (CDCl₃): δ 0.93-0.96 (6H, m), 1.27 (3H, t), 1.95-2.02 (1H,m), 3.65 (3H, s), 3.90 (3H, s), 3.90 (3H, s), 3.99 (2H, d), 4.34 (2H,q), 6.15 (1H, s), 6.38 (2H, s), 6.49 (2H, brs), 6.76 (1H, s).

[0378] EIMS: m/z 450 (M⁺).

[0379] (4c) In the same manner as in Example 3 (3c), the title compound(45 mg, 31%) was prepared as a yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isobutoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(143 mg) prepared in step (4b).

[0380]¹H-NMR (DMSO-d₆): δ 0.87 (3H, d), 0.89 (3H, d), 1.88-1.95 (1H, m),3.83 (3H, s), 3.85 (3H, s), 3.98 (2H, dd), 6.57 (2H, s), 7.18 (1H, s),7.65 (1H, s), 11.16 (1H, brs).

[0381] EIMS: m/z 404 (M⁺)

Example 5

[0382] 2-(Hexyloxycarbonyloxymethyl)-7,8-dimethoxy-4 (5H) 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0383] (5a) In the same manner as in Example 3 (3a), provided that hexylchloroformate (0.2 ml) was used instead of ethyl chloroformate, ethyl2-(hexyloxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(168 mg, 83%) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (140 mg).

[0384]¹H-NMR (CDCl₃): δ 0.86-0.90 (3H, m), 1.20-1.32 (6H, m), 1.44 (3H,t), 1.58-1.67 (2H, m), 4.00 (3H, s), 4.03 (3H, s), 4.18 (2H, t), 4.50(2H, q), 6.20 (2H, s), 7.01 (1H, s), 7.65 (1H, s)

[0385] EIMS: m/z 508 (M⁺).

[0386] (5b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(hexyloxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(149 mg, 96%o) was prepared as a yellow oil from ethyl2-(hexyloxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(165 mg) prepared in step (5a).

[0387]¹H-NMR (CDCl₃): δ 0.88 (3H, t), 1.27 (3H, t), 1.31-1.43 (6H, m),1.62-1. 69 (2H, m), 3.66 (3H, s), 3.90 (3H, s), 4.20 (2H, t), 4.34 (2H,q), 6.15 (1H, s), 6.37 (2H, s), 6.50 (2H, brs), 6.77 (1H, s).

[0388] EIMS: m/z 478 (M⁺)

[0389] (5c) In the same manner as in Example 3 (3c), the title compound(88 mg, 68%0) was prepared as yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(hexyloxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(145 mg) prepared in step (3b).

[0390]¹H-NMR (DMSO-d₆): δ 0.83 (3H, t), 1.24-1.28 (6H, m), 1.58-1.62(2H, m), 3.84 (3H, s), 3.86 (3H, s), 4.17 (2H, t), 6.56 (2H, s), 7.18(1H, s), 7.65 (1H, s), 11.16 (1H, brs).

[0391] EIMS: m/z 432 (M⁺)

Example 6

[0392] 2-(n-Butoxycarbonyloxymethyl)-7,8-dimethoxy-4 (5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0393] (6a) In the same manner as in Example 3 (3a), provided thatn-butyl chloroformate (0.26 ml) was used instead of ethyl chloroformate,ethyl2-(n-butoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(166 mg, 86%) was prepared as a yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (140 mg).

[0394]¹H-NMR (CDCl₃): δ 0.94 (3H, t), 1.35-1.41 (2H, m), 1.44 (3H, t),1.61-1.68 (2H, m), 4.00 (3H, s), 4.03 (3H, s), 4.19 (2H, t), 4.50 (2H,q), 6.20 (2H, s), 7.02 (1H, s), 7.66 (1H, s).

[0395] EIMS: m/z 480 (M⁺).

[0396] (6b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-'dimethoxybenzoyl)-2-(n-butoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(150 mg, 100%) was prepared as a yellow oil from ethyl2-(n-butoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(160 mg) prepared in step (6a).

[0397]¹H-NMR (CDCl₃) (0.83 (3H, t), 1.27 (3H, t), 1.36-1.42 (2H, m),1.63-1.69 (2H, m), 3.66 (3H, s), 3.91 (3H, s), 4.20 (2H, t), 4.34 (2H,q), 6.15 (1H, s), 6.38 (2H, s), 6.50 (2H, brs), 6.76 (1H, s).

[0398] EIMS: m/z 450 (M⁺).

[0399] (6c) In the same manner as in Example 3 (3c), the title compound(78 mg, 64%) was prepared as yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(n-butoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(150 mg) prepared in step (6b).

[0400]¹H-NMR (DMSO-d₆): (0.87 (3H, t), 1.28-1.36 (2H, m), 1.55-1.62 (2H,m), 3.84 (3H, s), 3.85 (3H, s), 4.18 (2H, t), 6.56 (2H, s), 7.17 (1H,s), 7.64 (1H, s), 11.16 (1H, brs).

[0401] EIMS: m/z 404 (M⁺).

Example 7

[0402] 2-(Isopropoxycarbonyloxymethyl)-7,8-dimethoxy-4(5H) 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0403] (7a) In the same manner as in Example 3 (3a), provided that 1Mtoluene solution (6 ml) of isopropyl chloroformate was used instead ofethyl chloroformate, a 2:1 mixture (906 mg) of ethyl2-(isopropoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylateand ethyl2-(isopropoxycarbonyl)-5(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylatewas prepared as a light yellow foam from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (700 mg).

[0404]¹H-NMR (CDCl₃): δ 1.29 (6H, d), 1.43-1.50 (3H, m), 4.01-4.04 (6H,m), 4.47-4.55 (2/3H, m), 5.28-5.35 (1/3H, m), 6.19 (4/3H, s), 7.01(2/3H, s), 7.04 (1/3H, s), 7.65 (2/3H, s), 7.67 (1/3H, s).

[0405] (7b) The 2:1 mixture (870 mg) of ethyl2-(isopropoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylateand ethyl2-(isopropoxycarbonyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylateprepared in step (7a) was reacted in the same manner as in Example 3(3a). The reaction product was purified by column chromatography onsilica gel (hexane/ethyl acetate) to give a 4 : 1 mixture (612 mg) ofethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylateand ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyl)-2H-1,2,3-triazole-4-carboxylateas a light yellow foam.

[0406]¹H-NMR (CDCl₃) δ 1.25-1.30 (3H, m), 1.31 (6H, d), 3.66 (3H, s),3.90 (3H, s), 4.32-4.39 (2H, m), 4.90-4.96 (4/5H, m), 5.30-5.46 (1/5H,m), 6.14 (1H, s), 6.36 (8/5H, s), 6.49 (2H, brs), 6.77 (1H, s).

[0407] (7c) In the same manner as in Example 3 (3c), the title compound(450 mg, 75%) was prepared as light yellow powder from the 4:1 mixture(610 mg) of ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylateand ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyl)-2H-1,2,3-triazole-4-carboxylateprepared in step (7b).

[0408]¹H-NMR (DMSO-d₆): δ 1.25 (6H, d), 3.84 (3H, s), 3.85 (3H, s),4.83-4.88 (1H, m), 6.66 (2H, s), 7.18 (1H, s), 7.65 (1H, s), 11.18 (1H,s).

Example 8

[0409] 2-(Benzoyloxymethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0410] (8a) In the same manner as in Example 3 (3a), provided thatbenzoyl chloride (0.28 ml) was used instead of ethyl chloroformate, acrude product of ethyl2-(benzoyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(230 mg) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (210 mg).

[0411] (8b) In the same manner as in Example 3 (3b), a crude product ofethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(benzoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(195 mg) was prepared as a yellow oil from the crude product of2-(benzoyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(230 mg) prepared in step (8a).

[0412] (8c) In the same manner as in Example 3 (3c), the title compound(40 mg, yield in three steps 56%) was prepared as yellow powder from thecrude product of ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(benzoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate prepared in step (8b).

[0413]¹H-NMR (DMSO-d₆): δ 3.82 (3H, s), 3.84 (3H, s), 6.80 (2H, s), 7.14(1H, s), 7.56 (2H, t), 7.62 (1H, s), 7.72 (1H, t), 8.01 (2H, d), 11.14(1H, brs)

Example 9

[0414] 2-(Lauroyloxymethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0415] (9a) In the same manner as in Example 3 (3a), provided thatlauroyl chloride (0.37 ml) was used instead of ethyl chloroformate.Thus, ethyl2-(lauroyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (190 mg, 85%) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-tr iazole-4-carboxylate(Synthesis Example 2) (140 mg).

[0416]¹H-NMR (CDCl₃): δ 0.88 (3H, t), 1.20-1.30 (16H, m), 1.44 (3H, t),1.55-1.65 (2H, m), 2.35 (2H, t), 4.01 (3H, s), 4.03 (3H, s), 4.50 (2H,q), 6.19 (2H, s), 7.03 (1H, s), 7.65 (1H, s)

[0417] EIMS: m/z 562 (M⁺)

[0418] (9b) In the same manner as in Example 3 (3b), ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(lauroyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(157 mg, 96%) was prepared as a yellow oil from ethyl2-lauroyloxymethyl-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(172 mg) prepared in step (9a).

[0419]¹H-NMR (CDCl₃): δ 0.86 (3H, t), 1.24-1.29 (16H, m), 1.27 (3H, t),1.55-1.65 (2H, m), 2.38 (2H, t), 3.66 (3H, s), 3.90 (3H, s), 4.34 (2H,q), 6.15 (1H, s), 6.36 (2H, s), 6.50 (2H, brs), 6.75 (1H, s).

[0420] EIMS: m/z 532 (M⁺)

[0421] (9c) In the same manner as in Example. 3 (3c), the title compound(95 mg, 70%) was prepared as a yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(lauroyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(150 mg) prepared in step (9b).

[0422]¹H-NMR (DMSO-d₆): δ 0.83 (3H, t), 1.15-1.20 (16H, m), 1.51 (2H,m), 2.41 (2H, t), 3.84 (3H, s) 3.85 (3H, s), 6.54 (2H, s), 7.18 (1H, s),7.65 (1H, s), 11.17 (1H, brs).

[0423] EIMS: m/z 486 (M⁺)

Example 10

[0424] 7,8-Dimethoxy-4(5H),10-dioxo-2-(palmitoyloxymethyl)-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0425] (10a) In the same manner as in Example 3 (3a) provided thatpalmitoyl chloride (0.49 ml) was used instead of ethyl chloroformate,ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(palmitoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(194 mg, 79%) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2, 3-triazole-4-carboxylate(Synthesis Example 2) (140 mg).

[0426]¹H-NMR (CDCl₃): δ 0.88 (3H, t), 1.20-1.30 (24H, m), 1.44 (3H, t),1.55-1.59 (2H, m), 2.35 (2H, t), 4.01 (3H, s), 4.03 (3H, s), 4.50 (2H,q), 6.19 (2H, s), 7.03 (1H, s), 7.65 (1H, s).

[0427] EIMS: m/z 618 (M⁺)

[0428] (10b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(palmitoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(158 mg, 88%) was prepared as a yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(palmitoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(190 mg) prepared in step (10a).

[0429]¹H-NMR (CDCl₃): δ 0.88 (3H, t), 1.24-1.29 (24H, m), 1.27 (3H, t),1.60-1.65 (2H, m), 2.38 (2H, t), 3.66 (3H, s), 3.91 (3H, s), 4.34 (2H,q), 6.15 (1H, s), 6.36 (2H, s), 6.50 (2H, brs), 6.76 (1H, s).

[0430] EIMS: m/z 588 (M⁺).

[0431] (10c) In the same manner as in Example 3 (3c), the title compound(117 mg, 82%) was prepared as yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(palmitoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(155 mg) prepared in step (10b).

[0432]¹H-NMR (DMSO-d₆): (0.84 (3H, t), 1.14-1.21 (24H, m), 1.51 (2H, m),2.41 (2H, t), 3.84 (3H, s), 3.85 (3H, s), 6.54 (2H, s), 7.18 (1H, s),7.65 (1H, s), 11.18 (1H, brs).

[0433] EIMS: m/z 542 (M⁺)

Example 11

[0434] 2-(4-Chlorobutyryloxymethyl)-7,8-dimethoxy-4(5H)10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0435] (11a) In the same manner as in Example 3 (3a) provided that4-chlorobutyryl chloride (0.36 ml) was used instead of ethylchloroformate, ethyl2-(4-chlorobutyryloxymethyl)-5(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(312 mg, 80° C.) was prepared as a light yellow foam from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (280 mg).

[0436]¹H-NMR (CDCl₃) δ 1.45 (3H, t), 2.05-2.14 (2H, m), 2.55-2.64 (2H,m), 3.55-3.60 (2H, m), 4.02 (3H, s), 4.03 (3H, s), 4.50 (2H, q), 6.22(2H, s), 7.03 (1H, s), 7.65 (1H, s).

[0437] EIMS: m/z 484 (M⁺)

[0438] (11b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-chlorobutyryloxymethyl)-2H-1,2,3-triazole-4-carboxylate(270 mg, 91%) was prepared as a yellow oil from ethyl2-(4-chlorobutyryloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(315 mg).

[0439]¹H-NMR (CDCl₃): δ 1.24-1.29 (3H, m), 2.12 (2H, m), 2.60 (2H, t),3.58-3.61 (2H, m), 3.65 (3H, s), 3.91 (3H, s), 4.34 (2H, q), 6.15 (1H,s), 6.38 (2H, s), 6.51 (2H, brs), 6.74 (1H, s).

[0440] EIMS: m/z 454 (M⁺).

[0441] (11c) In the same manner as in Example 3 (3c), the title compound(180 mg, 74%) was prepared as yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-chlorobutyryloxymethyl-2H-1,2,3-triazole-4-carboxylate(270 mg).

[0442]¹H-NMR (DMSO-d₆): δ 1.96-2.03 (2H, m), 2.38 (2H, t), 3.66 (2H, t),3.83 (3H, s), 3.85 (3H, s), 6.54 (2H, s), 7.15 (1H, s), 7.63 (1H, s),11.14 (1H, brs)

[0443] EIMS: m/z 408 (M⁺).

Example 12

[0444] 2-(4-Aminobenzoyloxymethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0445] (12a) In the same manner as in Example 3 (3a), provided thatp-nitrobenzoyl chloride (223 mg) was used instead of ethylchloroformate, ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-nitrobenzoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (118 mg, 56%) was prepared as a light yellow foam fromethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (140 mg).

[0446]¹H-NMR (CDCl₃) δ 1.45 (3H, t), 4.00 (3H, s), 4.03 (3H, s), 4.51(2H, q), 6.48 (2H, s), 7.06 (1H, s), 7.62 (1H, s), 8.20 (2H, d), 8.30(2H, d).

[0447] EIMS: m/z 529 (M⁺).

[0448] (12b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-aminobenzoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(100 mg, 98%) was prepared as a yellowish brown oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-nitrobenzoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (115 mg) prepared in step (12b).

[0449]¹H-NMR (CDCl₃): δ 1.29 (3H, t), 3.54 (3H, s), 3.89 (3H, s), 4.15(2H, brs), 4.33 (2H, q), 6.14 (1H, s), 6.40 (2H, brs), 6.56 (2H, s),6.56-6.67 (2H, m), 6.76 (1H, s), 7.83-7.91 (2H, m).

[0450] EIMS: m/z 469 (M⁺).

[0451] (12c) In the same manner as in Example 3 (3c), the title compound(54 mg, 59%) was prepared as yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-aminobenzoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(102 mg) prepared in step (12b).

[0452]¹H-NMR (DMSO-d₆): δ 3.83 (3H, s), 3.85 (3H, s), 6.21 (2H, s), 6.56(2H, d), 6.68 (2H, s), 7.16 (1H, s), 7.64 (1H, s), 7.67 (2H, d), 11.14(1H, brs)

[0453] EIMS: m/z 423 (M⁺).

Example 13

[0454] 7,8-Dimethoxy-4(5H), 10-dioxo-2-(3-pyridylcarbonyloxymethyl)-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0455] (13a) In the same manner as in Example 3 (3a), provided thatthionyl chloride (0.06 ml) was used instead of ethyl chloroformate,ethyl2-chloromethyl-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(146 mg, 92%) was prepared as a light yellow foam from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (140 mg)

[0456]¹H-NNR (CDCl₃): δ 1.45 (3H, t), 4.00 (3H, s), 4.03 (3H, s), 5.98(2H, s), 7.04 (1H, s), 7.66 (1H, s).

[0457] EIMS: m/z 398 (M⁺).

[0458] (13b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-chloromethyl-2H-1,2,3-triazole-4-carboxylate (120 mg, 93%) was prepared as a light yellowoil from ethyl2-chloromethyl-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(140 mg) prepared in step (13a).

[0459]¹H-NMR (CDCl₃): δ 1.28 (3H, t), 3.66 (3H, s), 3.91 (3H, s), 4.34(2H, q), 6.15 (3H, s), 6.42 (2H, brs), 6.73 (1H, s).

[0460] EIMS: m/z 368 (M⁺).

[0461] (13c) In the same manner as in Example 3 (3c), 2-chloromethyl-7,8-dimethoxy-4 (5H), 10-dioxo-2H-1,2,3-triaz olo[4,5-c][1]benzazepine (66mg, 66%) was prepared as light yellow powder form ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-chloromethyl-2H-1,2,3-triazole-4-carboxylate(114 mg) prepared in step (13b).

[0462]¹H-NMR (DMSO-d₆): (3.84 (3H, s) 3.85 (3H, s), 6.68 (2H, s), 7.17(1H, s), 7.64 (1H, s), 11.16 (1H, brs)

[0463] EIMS: m/z 322 (M⁺).

[0464] (13d) 2-Chloromethyl-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine (47 mg) prepared in step(13c) was dissolved in N,N-dimethylformamide (5 ml).Tetra-n-butylammonium bromide (10.5 mg), nicotinic acid (20 mg), andpotassium carbonate (34 mg) were added to the solution. The mixture wasstirred at 70° C. for 1.5 hr. After the mixture was allowed to stand forcooling, the reaction solution was post-treated by a conventional methodand subjected to separation and purification to give the title compound(41 mg, 67%) as a light yellow powder.

[0465]¹H-NMR (DMSO-d₆): δ 3.84 (3H, s), 3.85 (3H, s), 6.83 (2H, s), 7.16(1H, s), 7.60 (1H, dd), 7.64 (1H, s), 8.35 (1H, ddd), 8.86 (1H, dd),9.12 (1H, d), 11.16 (1H, brs).

[0466] FABMS: m/z 410 (M⁺+1).

Example 14

[0467] 7,8-Dimethoxy-4 (5H), 10-dioxo-2-(4-pyridylcarbonyloxymethyl)-2H-1,2 3-triazolo[4,5-c][1]benzazepine

[0468] (14a) In the same manner as in Example 13 (13d), provided thatisonicotinic acid (24 mg) was used instead of nicotinic acid, the titlecompound (30 mg, 46%) was prepared as light yellow powder from2-chloromethyl-7,8-dimethoxy-4 (5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benz azepine (52 mg) prepared instep (13c).

[0469]¹H-NMR (DMSO-d₆): δ 3.83 (3H, s), 3.85 (3H, s), 6.84 (2H, s), 7.17(1H, s), 7.64 (1H, s), 7.87 (2H, d), 8.83 (2H, d), 11.18 (1H, brs).

[0470] FABMS: m/z 410 (M⁺+1).

Example 15

[0471] 2-(1-Isobutyryloxyethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0472] (15a) In the same manner as in Example 3 (3a), provided thatacetaldehyde (0.13 ml) and thionyl chloride (0.7 ml) were usedrespectively instead of paraformaldehyde and ethyl chloroformate, ethyl2-(1-chloroethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (736 mg, 74%) was prepared as a light yellow foamfrom ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (840 mg).

[0473]¹H-NMR (CDCl₃): (1.45 (3H, t), 2.14 (3H, d), 4.01 (3H, s), 4.03(3H, s), 4.50 (2H, q), 6.42 (1H, q), 7.06 (1H, s), 7.64 (1H, s).

[0474] LCMS: m/z 413 (M⁺+1).

[0475] (15b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-chloroethyl)-2H-1,2,3-triazole-4-carboxylate(545 mg, 80%) was prepared as a light yellow foam from ethyl2-(1-chloroethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(735 mg) prepared in step (15a).

[0476]¹H-NMR (CDCl₃): δ 1.28 (3H, t), 2.28 (3H, d), 3.65 (3H, s), 3.91(3H, s), 4.35 (2H, q), 6.15 (1H, s), 6.51 (2H, brs), 6.6 (1H, q), 6.75(1H, s).

[0477] LCMS: m/z 383 (M⁺+1).

[0478] (15c) In the same manner as in Example 3 (3c),2-(1-chloroethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine (426 mg, 90%) was prepared as a light yellowpowder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-chloroethyl)-2H-1,2,3-triazole-4-carboxylate(540 mg) prepared in step (15b).

[0479]¹H-NMR (DMSO-d₆) δ 2.20 (3H, d), 3.84 (3H, s), 3.86 (3H, s), 7.18(1H, s), 7.21 (1H, q), 7.65 (1H, s), 11.19 (1H, s).

[0480] FABMS: m/z 337 (M⁺+1).

[0481] (15d) In the same manner as in Example 13 (13d), provided thatisobutyric acid (0.023 ml) was used instead of ethyl chloroformate.Thus, the title compound (32 mg, 41%) was prepared as a light yellowpowder from 2-(1-chloroethyl)-7,8-dimethoxy-4 (5H),10-dioxo-2H-1,2,3-triaz olo[4,5-c][1]benzazepine (67 mg) prepared instep (15c).

[0482]¹H-NMR (DMSO-d₆) 1.05 (3H, d), 1.10 (3H, d), 1.88 (3H, d),2.60-2.67 (1H, m), 3.84 (3H, s) 3.85 (3H, s), 7.18 (1H, s), 7.23 (1H,q), 7.65 (1H, s), 11.16 (1H, brs).

[0483] LCMS: m/z 389 (M⁺+1).

Example 16

[0484] 7,8-Dimethoxy-2-(4-methoxyphenylacetoxymethyl)-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0485] (16a) In the same manner as in Example 3 (3a), provided that amethylene chloride solution of acid chloride prepared fromp-methoxyphenylacetic acid (400 mg) and thionyl chloride (0.88 ml) wasused instead of ethyl chloroformate, ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-methoxyphenylacetoxymethyl)-2H-1,2,3-triazole-4-carboxylate(210 mg, 66%) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (210 mg).

[0486]¹H-NMR (CDCl₃): δ 1.45 (3H, t), 3.61 (2H, s), 3.79 (3H, s), 4.00(3H, s), 4.03 (3H, s), 4.50 (2H, q), 6.20 (2H, s), 6.84 (2H, d), 7.03(1H, s), 7.14 (2H, d), 7.64 (1H, s).

[0487] LCMS: m/z 528 (M⁺).

[0488] (16b) In the same manner as in Example 3 (3b), ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-methoxyphenylacetoxymethyl)-2H-1,2,3-triazole-4-carboxylate (180mg, 95%6) was prepared as a yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-methoxyphenylacetoxymethyl)-2H-1,2,3-triazole-4-carboxylate(200 mg) prepared in step (16a).

[0489]¹H-NMR (CDCl₃): δ 1.28 (3H, t), 3.60 (3H, s), 3.64 (2H, s), 3.79(3H, s), 3.91 (3H, s), 4.35 (2H, q), 6.15 (1H, s), 6.37 (2H, s), 6.50(2H, brs), 6.73 (1H, s), 6.84 (2H, d), 7.17 (2H, d).

[0490] LCMS: m/z 499 (M⁺+1).

[0491] (16c) In the same manner as in Example 3 (3c), the title compound(118 mg, 75%) was prepared as a yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-methoxyphenylacetoxymethyl)-2H-1,2,3-triazole-4-carboxylate(175 mg) prepared in step (16b).

[0492]¹H-NMR (DMSO-d₆): δ 3.71 (3H, s), 3.74 (3H, s), 3.85 (3H, s), 6.56(2H, s), 6.85 (2H, d), 7.18 (1H, s), 7.18 (2H, d), 7.65 (1H, s), 11.17(1H, brs).

[0493] LCMS: m/z 453 (M⁺+1).

Example 17

[0494] 7,8-Dimethoxy-2-(N-(2-(N,N-dimethylamino)ethyl)carbamoyloxymethyl)-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]ben zazepine

[0495] (17a) In the same manner as in Example 3 (3a), provided thatp-nitrophenyl chloroformate (806 mg) was used instead of ethylchloroformate, ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-nitrophenoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(778 mg, 71%) was prepared from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-tri azole-4-carboxylate(Synthesis Example 2) (700 mg).

[0496]¹H-NMR (CDCl₃): δ 1.46 (3H, t), 4.01 (3H, s), 4.03 (3H, s), 4.52(2H, q), 6.34 (2H, s), 7.05 (1H, s), 7.40 (2H, d), 7.64 (1H, s), 8.30(2H, d).

[0497] (17b) N,N-dimethylethylenediamine (0.02 ml) was added to asolution of ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-nitrophenoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate(83 mg), prepared in step (17a), in methylene chloride solution (1.5 ml)under ice cooling. The mixture was stirred for 2 hr. The reactionsolution was post-treated by a conventional method and subjected toseparation and purification to give ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(N-(2-(N,N-dimethylamino)ethyl)carbamoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (64 mg, 85%).

[0498]¹H-NMR (CDCl₃): δ 1.43 (3H, t), 2.21 (6H, s), 2.41 (2H, t),3.20-3.30 (2H, m), 4.00 (3H, s), 4.03 (3H, s), 4.49 (2H, q), 5.49 (1H,s), 6.18 (2H, s), 7.02 (1H, s), 7.65 (1H, s).

[0499] (17c) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(N-(2-(N,N-dimethylamin O) ethyl)carbamoyloxymethyl)-2H-1,2,3-triazole-4-carboxyl ate (56 mg, 100%) wasprepared from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(N-(2-(N,N-dimethylamino)ethyl)carbamoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (59 mg) preparedin step (17b).

[0500]¹H-NMR (CDCl₃): δ 1.25 (3H, t), 2.75 (6H, s), 3.05-3.15 (2H, m),3.58-3.68 (2H, m), 3.67 (3H, s), 3.90 (3H, s), 4.32 (2H, q), 6.15 (1H,s), 6.37 (2H, s), 6.50 (2H, brs), 6.75 (1H, s).

[0501] FABMS: m/z 465 (M⁺+1).

[0502] (17d) In the same manner as in Example 3 (3c), the title compound(28 mg, 56%) was prepared as a white powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(N-(2-(N,N-dimethylamino)ethyl)carbamoyloxymethyl)-2H-1,2,3-triazole-4-carboxylate (56 mg)prepared in step (17c).

[0503]¹H-NMR (DMSO-d₆): δ 2.77 (6H, s), 3.10-3.20 (2H, m), 3.35-3.45(2H, m), 3.84 (3H, s), 3.86 (3H, s), 6.49 (2H, s)1 7.20 (1H, s), 7.65(1H, s), 7.98 (1H, t), 11.16 (1H, s)

[0504] EIMS: m/z 418 (M⁺+1).

Example 18

[0505] 2-(Diethoxvphosphoryloxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0506] (18a) In the same manner as in Example 3 (3a), provided thatdiethyl chlorophosphate (0.12 ml) was used instead of ethylchloroformate, a crude product of ethyl2-(diethoxyphosphoryloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(205 mg) was prepared from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (255 mg).

[0507] (18b) In the same manner as in Example 3 (3b), a crude product ofethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(diethoxyphosphoryloxymethyl)-2H-1,2,3-triazole-4-carboxylate(186 mg) was prepared from the crude product of ethyl2-(diethoxyphosphoryloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(205 mg) prepared in step (18a).

[0508] (18c) In the same manner as in Example 3 (3c), the title compound(73 mg, yield in three steps 41%) was prepared from the crude product ofethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(diethylphosphoryloxymethyl)-2H-1,2,3-triazole-4-carboxylate(179 mg) prepared in step (18b).

[0509]¹H-NMR (DMSO-d₆): δ 1.20 (6H, t), 3.84 (3H, s), 3.86 (3H, s),4.00-4.10 (4H, m), 6.41 (2H, d), 7.19 (1H, s), 7.66 (1H, s), 11.18 (1H,s).

[0510] FABMS: m/z 441 (M⁺+1).

Example 19

[0511] 7,8-Dimethoxy-4(5H), 10-dioxo-2-(1-(3-pentyloxycarbonyloxy)propyl)-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0512] (19a) Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (2.1 g) and p-toluenesulfonic acid monohydrate (23mg) were suspended in methylene chloride (60 ml) under an argonatmosphere. Propionaldehyde (0.48 ml) was added to the suspension. Themixture was stirred at room temperature for 10 min.1,1′-Carbonyldiimidazole (1.07 g) was added thereto, and the mixture wasstirred at room temperature for 10 min. The mixture was post-treated bya conventional method and then subjected to separation and purificationto give ethyl2-1-(imidazolylcarbonyloxy)propyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(2.35 g, 78%) as a light yellow foam.

[0513]¹H-NMR (CDCl₃) δ 0.95 (3H, t), 1.45 (3H, t), 2.34-2.46 (2H, m),4.01 (3H, s), 4.05 (3H, s), 4.50 (2H, q), 6.94 (1H, t), 7.08 (1H, m),7.09 (1H, s), 7.39-7.40 (1H, m), 7.60 (1H, s), 8.12 (1H, m).

[0514] (19b) Ethyl2-(1-(imidazolylcarbonyloxy)propyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H—1,2,3-triazole-4-carboxylate(377 mg) prepared in step (19a) was dissolved in toluene (12 ml).3-Pentanol (1.6 ml) was added to the solution. The mixture was heatedunder reflux for 20 hr. The mixture was post-treated by a conventionalmethod and subjected to separation and purification to give ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(1-(3-pentyloxycarbonyloxy)propyl)-2H-1,2,3-triazole-4-carboxylate(280 mg) as a light yellow oil.

[0515]¹H-NMR (CDCl₃): δ 0.82-0.99 (9H, m), 1.44 (3H, t), 1.56-1.79 (4H,m), 2.18-2.29 (2H, m), 4.00 (3H, s), 4.03 (3H, s), 4.50 (2H, q),4.54-4.60 (1H, m), 6.62 (1H, t), 7.04 (1H, s), 7.62 (1H, s).

[0516] LCMS: m/z 522 (M⁺).

[0517] (19c) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(3-pentyloxycarbonyloxy)propyl)-2H-1,2,3-triazole-4-carboxylate (185 mg, yield in twosteps 5096) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(1-(3-pentyloxycarbonyloxy)propyl)-2H-1,2,3-triazole-4-carboxylate (270 mg)prepared in step (19b).

[0518]¹H-NMR (CDCl₃): δ 0.85 (3H, t), 0.92 (3H, t), 0.97 (3H, t), 1.28(3H, t), 1.57-1.67 (4H, m), 2.30-2.49 (2H, m), 3.64 (3H, s), 3.90 (3H,s), 4.34 (2H, q), 4.56-4.62 (1H, m), 6.14 (1H, s), 6.48 (2H, brs), 6.77(1H, t) 6.78 (1H, s).

[0519] LCMS: m/z 493 (M⁺+1).

[0520] (19d) In the same manner as in Example 3 (3c), the title compound(135 mg, 83%) was prepared as light yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(3-pentyloxycarbonyloxy)propyl)-2H-1,2,3-triazole-4-carboxylate(180 mg) prepared in step (19c).

[0521]¹H-NMR (CDCl₃): δ 0.84 (3H, t), 0.92 (3H, t), 0.98 (3H, t),1.55-1.67 (4H, m), 2.39-2.50 (2H, m), 4.00 (3H, s), 4.05 (3H, s), 4.60(1H, quintet), 6.75 (1H, s), 6.92 (1H, t), 7.88 (1H, s), 9.54 (1H, s).

[0522] LCMS: m/z 447 (M⁺)

Example 20

[0523] 2-(1-Isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0524] (20a) Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (1.07 g) and p-toluenesulfonic acid monohydrate(53 mg) were suspended in methylene chloride (10 ml) under an argonatmosphere. Isobutyl aldehyde (330 mg) was added to the suspension. Themixture was stirred at room temperature for 25 min.1,1′-carbonyldiimidazole (744 mg) and methylene chloride (5.0 ml) wereadded thereto, and the mixture was stirred at room temperature for 25min. Isopropyl alcohol (920 mg) was added thereto, and the mixture wasstirred at room temperature for 3 hr and then refluxed for 21 hr. Themixture was post-treated by a conventional method and subjected toseparation and purification to give ethyl2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylateas a light yellow foam (520 mg, 34%).

[0525]¹H-NMR (CDCl₃): δ 0.72 (3H, d), 1.05 (3H, d), 1.25 (3H, d), 1.28(3H, d), 1.44 (3H, t), 2.56 (1H, m), 4.00 (3H, s), 4.08 (3H, s), 4.49(2H, q), 4.85 (1H, m), 6.35 (1H, d), 7.06 (1H, s), 7.62 (1H, s).

[0526] (20a′) Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (50 g) was suspended in ethyl acetate (500 ml).Isobutyl aldehyde (20 ml) was added to the suspension at 25° C. under anitrogen stream. The mixture was stirred at that temperature for 20 min.

[0527] Next, sodium iodide (21.4 g) and potassium carbonate (78.9 g)were added thereto. Further, 50 ml of isopropyl chloroformate was addedthereto, and a reaction was allowed to proceed with stirring at 60° C.for 45 hr.

[0528] Ethyl acetate (100 ml) was added to the reaction solution. Themixture was washed twice with 750 ml of water and then washed with a 20%aqueous sodium chloride solution (500 ml). The organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure.

[0529] The residue was crystallized from aqueous methanol to give ethyl2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(70.2 g, 96.7%). The ¹H-NMR spectrum of this compound was the same asthat of the compound prepared in step (20a).

[0530] (20a″ ) Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (5.00 g) was suspended in ethyl acetate (50 ml).1-Chloro-2-methylpropylisopropyl carbonate (8.34 g), sodium iodide (2.14g), and potassium carbonate (7.89 g) were added to the suspension at 25°C. under a nitrogen stream. A reaction was allowed to proceed withstirring at 60° C. for 96 hr.

[0531] Ethyl acetate (10 ml) was added to the reaction solution. Themixture was washed twice with water (75 ml) and then washed with a 20%aqueous sodium chloride solution (50 ml). The organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (n-hexane/ethyl acetate) to give ethyl2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(0.89 g, 12.3%). The ¹H-NMR spectrum of this compound was the same asthat of the compound prepared in step (20a).

[0532] (20b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate(485 mg, 99%) was prepared as a light yellow foam from ethyl2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(520 mg) prepared in step (20a).

[0533]¹H-NMR (CDCl₃): δ 0.85 (3H, d), 1.14 (3H, d), 1.26 (3H, d), 1.28(3H, t), 1.31 (3H, d), 2.75 (1H, m), 3.81 (3H, s), 3.90 (3H, s), 4.34(2H, q), 4.86 (1H, m), 6.14 (1H, s), 6.49 (2H, brs), 6.51 (1H, d), 6.77(1H, s)

[0534] (20c) In the same manner as in Example 3 (3c), the title compound(273 mg, 62%) was prepared as a light yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate(485 mg) prepared in step (20b).

[0535]¹H-NMR (CDCl₃): δ 0.85 (3H, d), 1.15 (3H, d), 1.25 (3H, d), 1.31(3H, d), 2.80 (1H, m), 4.00 (3H, s), 4.05 (3H, s), 4.86 (1H, m), 6.68(1H, d), 6.73 (1H, s), 7.88 (1H, s), 9.47 (1H, brs).

[0536] LCMS: m/z 433 (M⁺+1).

Example 21

[0537] 2-(Acetoxymethyl)-7,8-dimethoxy-4 (5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0538] (21a) In the same manner as in Example 19 (a), provided thatparaformaldehyde (45 mg) and acetic anhydride (0.3 ml) were usedrespectively instead of propionaldehyde and 1,1′-carbonyldiimidazole,ethyl2-(acetoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(618 mg, 98%) was prepared as a light yellow foam from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2, 3-triazole-4-carboxylate(Synthesis Example 2) (525 mg).

[0539]¹H-NMR (CDCl₃): δ 1.45 (3H, t), 2.12 (3H, s), 4.01 (3H, s), 4.03(3H, s), 4.50 (2H, q), 6.19 (2H, s), 7.04 (1H, s), 7.65 (1H, s).

[0540] EIMS: m/z 422 (M⁺).

[0541] (21b) In the same manner as in Example 3 (3b), ethyl2-(acetoxymethyl)-5-(2-amino-4,5-dimethoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate(510 mg, 90%) was prepared as a yellow oil from ethyl2-(acetoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(610 mg) prepared in step (21a).

[0542]¹H-NMR (CDCl₃): δ 1.27 (3H, t), 2.15 (3H, s), 3.66 (3H, s), 3.91(3H, s), 4.34 (2H, q), 6.15 (1H, s), 6.35 (2H, s), 6.50 (2H, brs), 6.75(1H, s).

[0543] EIMS: m/z 392 (M⁺)

[0544] (21c) In the same manner as in Example 3 (3c), the title compound(360 mg, 84%) was prepared as yellow powder from ethyl2-(acetoxymethyl)-5-(2-amino-4,5-dimethoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate(492 mg) prepared in step (21b).

[0545]¹H-NMR (DMSO-d₆): δ 2.12 (3H, s), 3.83 (3H, s), 3.84 (3H, s), 6.52(2H, s), 7.14 (1H, s), 7.63 (1H, s), 11.2 (1H, brs).

[0546] EIMS: m/z 346 (M⁺).

Example 22

[0547] 2-(Isobutyryloxymethyl)-7,8-dimethoxy-4(5H)10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0548] (22a) In the same manner as in Example 19 (19a), provided thatparaformaldehyde (12 mg) and isobutyric anhydride (0.17 ml) were usedrespectively instead of propionaldehyde and 1,1′-carbonyldiimidazole,ethyl2-(isobutyryloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(178 mg, 99%) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (140 mg).

[0549]¹H-NMR (CDCl₃): δ 1.15 (3H, d), 1.21 (3H, d), 1.45 (3H, t),2.57-2.68 (1H, m), 4.01 (3H, s), 4.03 (3H, s), 4.50 (2H, q), 6.20 (2H,s), 7.03 (1H, s), 7.65 (1H, s).

[0550] (22b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isobutyryloxymethyl)-2H-1,2,3-triazole-4-carboxylate(510 mg, 90%) was prepared as a yellow oil from ethyl2-(isobutyryloxymethyl)-5(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(610 mg) prepared in step (22a).

[0551]¹H-NMR (CDCl₃): δ 1.18 (6H, d), 1.28 (3H, t), 2.61-2.66 (1H, m),3.65 (3H, s), 3.90 (3H, s), 4.34 (2H, q), 6.15 (1H, s), 6.36 (2H, s),6.50 (2H, brs), 6.75 (1H, s).

[0552] EIMS: m/z 420 (M⁺)

[0553] (22c) In the same manner as in Example 3 (3c), the title compound(360 mg, 84%) was prepared as yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isobutyryloxymethyl)-2H-1,2,3-triazole-4-carboxylate(492 mg) prepared in step (22b).

[0554]¹H-NMR (DMSO-d₆): δ 1.10 (6H, d), 2.62-2.69 (1H, m), 3.84 (3H, s)3.85 (3H, s), 6.54 (2H, s), 7.18 (1H, s), 7.64 (1H, s), 11.16 (1H, brs).

[0555] EIMS: m/z 374 (M⁺)

Example 23

[0556] 2-(n-Butyryloxymethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0557] (23a) In the same manner as in Example 19 (19a), provided thatparaformaldehyde (12 mg) and butyric anhydride (0.13 ml) were usedrespectively instead of propionaldehyde and 1,1′-carbonyldiimidazole,ethyl2-(n-butyryloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(178 mg, 99%) was prepared as a light yellow foam from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H—1,2,3-triazole-4-carboxylate(Synthesis Example 2) (140 mg).

[0558]¹H-NMR (CDCl₃): δ 0.92 (3H, t), 1.44 (3H, t), 1.61-1.71 (2H, m),2.44 (2H, t), 4.01 (3H, s), 4.03 (3H, s), 4.50 (2H, q), 6.20 (2H, s),7.03 (1H, s), 7.65 (1H, s).

[0559] EIMS: m/z 450 (M⁺).

[0560] (23b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(n-butyryloxymethyl)-2H-1,2,3-triazole-4-carboxylate(126 mg, 83%) was prepared as a yellow oil from ethyl2-(n-butyryloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(160 mg) prepared in step (23a).

[0561]¹H-NMR (CDCl₃): δ 0.95 (3H, t), 1.27 (3H, t), 1.64-1.70 (2H, m),2.37 (2H, t), 3.65 (3H, s), 3.91 (3H, s), 4.34 (2H, q), 6.15 (1H, s),6.36 (2H, s), 6.50 (2H, brs), 6.75 (1H, s).

[0562] EIMS: m/z 420 (M⁺).

[0563] (23c) In the same manner as in Example 3 (3c), the title compound(86 mg, 80%) was prepared as yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(n-butyryloxymethyl)-2H-1,2,3-triazole-4-carboxylate(120 mg) prepared in step (23b).

[0564]¹H-NMR (DMSO-d₆): δ 0.87 (3H, t), 1.51-1.60 (2H, m), 2.43 (2H, t),3.84 (3H, s), 3.85 (3H, s), 6.54 (2H, s), 7.17 (1H, s), 7.64 (1H, s),11.2 (1H, brs)

[0565] EIMS: m/z 374 (M⁺).

Example 24

[0566] 2-(3-Carboxypropionyloxymethyl)-7,8-dimethoxy-4(5H) 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0567] (24a) In the same manner as in Example 19 (19a), provided thatparaformaldehyde (15 mg) and a methylene chloride solution of an acidchloride prepared from a monobenzyl ester of succinic acid (520 mg) andthionyl chloride (0.91 ml) were used respectively instead ofpropionaldehyde and 1,1′-carbonyldiimidazole, ethyl2-(3-(benzyloxycarbonyl)propionyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(148 mg, 58%) was prepared from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (175 mg).

[0568]¹H-NMR (CDCl₃): δ 1.44 (3H, t), 2.69 (4H, s), 3.99 (3H, s), 4.02(3H, s), 4.49 (2H, q), 5.11 (2H, s), 6.19 (2H, s), 7.03 (1H, s),7.30-7.40 (5H, m), 7.63 (1H, s).

[0569] (24b) In the same manner as in Example 3 (3b) and (3c), the titlecompound (7 mg, 26%) was prepared from ethyl2-(3-(benzyloxycarbonyl)propionyloxymethyl)-5(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(100 mg) prepared in step (24a).

[0570]¹H-NMR (DMSO-d₆) δ 2.60 (4H, m), 3.83 (3H, s), 3.85 (3H, s), 6.54(2H, s), 7.17 (1H, s), 7.64 (1H, s), 11.16 (1H, s), 12.54 (1H, brs).

[0571] FABMS: m/z 405 (M⁺+1).

Example 25

[0572] 2-(Cyclohexylcarbonyloxymethyl)-7,8-dimethoxy-4 (5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0573] (25a) In the same manner as in Example 19 (19a), provided thatparaformaldehyde (15 mg) and cyclohexylcarbonyl chloride (0.54 ml) wereused respectively instead of propionaldehyde and1,1′-carbonyldiimidazole, ethyl2-(cyclohexylcarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(416 mg) was prepared from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (175 mg)).

[0574]¹H-NMR (CDCl₃): δ 1.20-2.00 (10H, m), 1.44 (3H, t), 2.35 (1H, m),4.00 (3H, s), 4.03 (3H, s), 4.49 (2H, q), 6.19 (2H, s), 7.03 (1H, s),7.65 (1H, s)

[0575] FABMS: m/z 491 (M⁺+1).

[0576] (25b) In the same manner as in Example 3 (3b) and (3c), the titlecompound (32 mg, 18%) was prepared from ethyl2-(cyclohexylcarbonyloxymethyl)-5(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(a) (200 mg) prepared in step (25a).

[0577]¹H-NMR (DMSO-d₆): δ1.16-1.90 (10H, m), 2.45 (1H, m), 3.83 (3H, s),3.85 (3H, s), 6.51 (2H, s), 7.16 (1H, s), 7.64 (1H, s), 11.15 (1H, s).

[0578] FABMS: m/z 415 (M⁺+1).

Example 26

[0579] 7,8-Dimethoxy-2-(3-methoxypentan-3-yl)-4(5H)10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0580] (26a) p-Toluenesulfonic acid monohydrate (20 mg) was added to asolution of 3-pentanone (3.1 ml) and trimethyl orthoformate (3.3 ml) inmethylene chloride (10 ml). The mixture was heated for one hr withstirring. This solution (4 ml) was added to a solution of ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (140 mg) in methylene chloride (2 ml). The mixturewas stirred at room temperature for one hr, and triethylamine (0.05 ml)was then added thereto. The mixture was post-treated by a conventionalmethod and subjected to separation and purification to give ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(3-methoxypentan-3-yl)-2H-1,2,3-triazole-4-carboxylate(140 mg, 78%) as a yellow powder. ¹H-NMR (CDCl₃): δ 0.75-0.79 (6H, m),1.45 (3H, t), 2.19-2.25 (4H, m), 2.97 (3H, s), 4.01 (3H, s), 4.04 (3H,s), 4.49 (2H, q), 7.10 (1H, s), 7.60 (1H, s).

[0581] FABMS: m/z 451 (M⁺+1).

[0582] (26b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(3-methoxypentan-3-yl)-2H-1,2,3-triazole-4-carboxylate(110 mg, 91%) from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(3-methoxypentan-3-yl)-2H-1,2,3-triazole-4-carboxylate(130 mg) prepared in step (26a).

[0583]¹H-NMR (CDCl₃): δ 0.87 (6H, t), 1.26 (3H, t), 2.33-2.45 (4H, m),3.13 (3H, s), 3.61 (3H, s), 3.90 (3H, s), 4.33 (2H, q), 6.15 (1H, s),6.49 (2H, brs), 6.74 (1H,

[0584] FABMS: m/z 421 (M⁺+1).

[0585] (26c) Ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(3-methoxypentan-3-yl)-2H-1,2,3-triazole-4-carboxylate(80 mg) was dissolved in isopropyl alcohol (1.5 ml) under an argonatmosphere. Potassium tert-butoxide (25 mg) was added to the solution.The mixture was stirred at room temperature for 15 min. The mixture waspost-treated by a conventional method and subjected to separation andpurification to give the title compound.(35 mg, 49%) as a yellow powder.

[0586]¹H-NMR (CDCl₃): δ 0.87 (6H, t), 2.42 (2H, q), 2.53 (2H, q), 3.13(3H, s), 4.00 (3H, s), 4.03 (3H, s), 6.66 (1H, s), 7.90 (1H, s), 9.14(1H, brs).

[0587] FABMS: m/z 374 (M⁺).

Example 27

[0588] 2-(4-Ethoxyheptan-4-yl)-7,8-dimethoxy-4(5H)10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0589] (27a) Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole4-carboxylate (Synthesis Example 2) (140 mg) and p-toluenesulfonic acidmonohydrate (2 mg) were suspended in methylene chloride (2 ml) under anargon atmosphere. 4-Heptane (0.14 ml) and triethyl orthoformate (0.17ml) were added to the suspension. The mixture was stirred at roomtemperature for 2 hr. Further, p-toluenesulfonic acid monohydrate (4.5mg) was added thereto. The mixture was stirred at room temperature for 2hr. The mixture was post-treated by a conventional method and subjectedto separation and purification to give ethyl2-(4-ethoxyheptan-4-yl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(160 mg, 82%) as a yellow powder.

[0590]¹H-NMR (CDCl₃): δ 0.90 (6H, t), 1.00-1.15 (2H, m), 1.04 (3H, t),1.26 1.28 (2H, m), 1.44 (3H, t), 2.05-2.21 (4H, m), 3.10 (2H, q), 4.01(3H, s), 4.04 (3H, s), 4.48 (2H, q), 7.08 (1H, s), 7.61 (1H, s)

[0591] EIMS: m/z 492 (M⁺).

[0592] (27b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-ethoxyheptan-4-yl)-2H-1,2,3-triazole-4-carboxylate (160 mg, 90%) was prepared as a yellow oil fromethyl2-(4-ethoxyheptan-4-yl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(190 mg) prepared in step (27a).

[0593]¹H-NMR (CDCl₃): δ 0.95 (6H, t), 1.10-1.19 (2H, m), 1.11 (3H, t),1.25 (3H, t), 1.35-1.38 (2H, m), 2.24-2.42 (4H, m), 3.25 (2H, q), 3.61(3H, s), 3.90 (3H, s), 4.32 (2H, q), 6.15 (1H, s), 6.50 (2H, brs), 6.74(1H,

[0594] EIMS: m/z 462 (M⁺).

[0595] (27c) In the same manner as in Example 26 (26c), the titlecompound (75 mg, 60%) was prepared as a yellow crystal powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-ethoxyheptan-4-yl)-2H-1,2,3-triazole-4-carboxylate (143 mg) prepared in step (27b).

[0596]¹H-NMR (CDCl₃): δ 0.96 (6H, t), 1.11-1.19 (2H, m), 1.13 (3H, t),1.34-1.43 (2H, m), 2.30-2.38 (2H, m), 2.44-2.52 (2H, m), 3.28 (2H, q),4.00 (3H, s), 4.05 (3H, s), 6.80 (1H, s), 7.90 (1H, s), 9.68 (1H, brs)

[0597] FABMS: m/z 417 (M⁺+1).

Example 28

[0598] 2-(Ethoxymethyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0599] (28a) Ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (210 mg) and p-toluenesulfonic acid monohydrate(62 mg) were suspended in methylene chloride (5 ml) under an argonatmosphere. Diethoxymethane (0.5 ml) was added to the suspension. Themixture was stirred at 80° C. for 2 hr. The mixture was post-treated bya conventional method and subjected to separation and purification togive ethyl2-(ethoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(242 mg, 99%0) as a yellow powder.

[0600]¹H-NMR (CDCl₃): δ 1.17 (3H, t), 1.45 (3H, t), 3.55 (2H, q), 4.00(3H, s), 4.03 (3H, s), 4.49 (2H, q), 5.62 (2H, s), 7.05 (1H, s), 7.64(1H, s)

[0601] EIMS: m/z 408 (M⁺).

[0602] (28b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxymethyl)-2H-1,2,3-triazole-4-carboxylate(178 mg, 88%) was prepared as a yellow oil from ethyl2-(ethoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(220 mg) prepared in step (28a).

[0603]¹H-NMR (CDCl₃): δ 1.21 (3H, t), 1.26 (3H, t), 3.63 (3H, s), 3.70(2H, q), 3.90 (3H, s), 4.43 (2H, q), 5.78 (2H, s), 6.15 (1H, s), 6.50(2H, brs), 6.73 (1H, s).

[0604] EIMS: m/z 378 (M⁺).

[0605] (28c) In the same manner as in Example 26 (26c), the titlecompound (116 mg, 92%) was prepared as a yellow powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxymethyl)-2H-1,2,3-triazole-4-carboxylate(142 mg) prepared in step (28b).

[0606]¹H-NMR (DMSO-d₆): δ 1.12 (3H, t), 3.64 (2H, q), 3.83 (3H, s), 3.85(31H, s), 5.94 (2H, s), 7.13 (1H, s), 7.65 (1H, s), 11.2 (1H, brs)

[0607] EIMS: m/z 332 (M⁺).

Example 29

[0608] 2-(Isopropoxymethyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0609] (29a) In the same manner as in Example 19 (19a), paraformaldehyde(42 mg) and isopropyl alcohol (0.092 ml) were used respectively insteadof propionaldehyde and 1,1′-carbonyldiimidazole. Thus, ethyl2-(isopropoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(215 mg, 85%) was prepared as a light yellow oil from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (210 mg).

[0610]¹H-NMR (CDCl₃): δ 1.17 (6H, d), 1.45 (3H, t), 3.74-3.80 (1H, m),4.00 (3H, s), 4.03 (3H, s), 4.49 (2H, q), 5.63 (2H, s), 7.04 (1H, s),7.64 (1H, s).

[0611] EIMS: m/z 422 (M⁺).

[0612] (29b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxymethyl)-2H-1,2,3-triazole-4-carboxylate(190 mg) was prepared as a yellow oil from ethyl2-(isopropoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(200 mg) prepared in step (29a).

[0613]¹H-NMR (CDCl₃): δ 1.17 (6H, d), 1.26 (3H, t), 3.63 (3H, s),3.80-3.90 (1H, m), 3.90 (3H, s), 4.43 (2H, q), 5.80 (2H, s), 6.16 (1H,s), 6.50 (2H, brs), 6.72 (1H, s).

[0614] EIMS: m/z 392 (M⁺).

[0615] (29c) In the same manner as in Example 26 (26c), the titlecompound (110 mg, 70%) was prepared as a yellow powder from ethylS-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxymethyl)-2H-1,2,3-triazole-4-carboxylate(180 mg) prepared in step (26b).

[0616]¹H-NMR (DMSO-d₆): δ 1.12 (6H, d), 3.84 (3H, s), 3.85 (3H, s),3.93-3.95 (1H, m), 5.96 (2H, s), 7.18 (1H, s), 7.66 (1H, s), 11.1 (1H,brs)

[0617] EIMS: m/z 346 (M⁺).

Example 30

[0618]2-(1-(1,3-Diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0619] (30a) In the same manner as in Example 19 (19a) provided thatisobutyl aldehyde (0.078 ml) was used instead of propionaldehyde, ethylimidazolylcarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(252 mg, 61%) was prepared from ethyl5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 2) (280 mg).

[0620]¹H-NMR (CDCl₃): δ 0.82 (3H, d), 1.12 (3H, d), 1.44 (3H, t),2.64-2.81 (1H, m), 4.01 (3H, s), 4.04 (3H, s), 4.50 (2H, q), 6.67 (1H,d), 7.08 (2H, m), 7.41 (1H, s), 7.59 (1H, s), 8.14 (1H, m).

[0621] LCMS:m/z 517 (M⁺+1).

[0622] (30b) In the same manner as in Example 19 (19b), provided that1,3-diethoxy-2-propanol (0.6 ml) was used instead of 3-pentanol, ethyl2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(165 mg, 44%) was prepared as a light yellow oil from ethyl2-(1-(1-imidazolylcarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(325 mg) prepared in step (30a).

[0623]¹H-NMR (CDCl₃): δ 0.71 (3H, d), 1.08-1.25 (9H, m), 1.45 (3H, t),2.49-2.61 (1H, m), 3.38-3.63 (8H, m), 4.01 (3H, s), 4.04 (3H, s), 4.50(2H, q), 4.92-4.94 (1H, m), 6.38 (1H, d), 7.06 (1H, s), 7.62 (1H, s).

[0624] LCMS: m/z 597 (M⁺+1).

[0625] (30c) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (177mg, 78%) was prepared as a light yellow oil from ethyl2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(240 mg) prepared in step (30b).

[0626]¹H-NMR (CDCl₃): δ 0.85 (3H, d), 1.08-1.21 (9H, m), 1.29 (3H, t),2.75-2.81 (1H, m), 3.40-3.72 (11H, m), 3.91 (3H, s), 4.34 (2H, q),4.92-4.97 (1H, m), 6.15 (1H, s), 6.50 (2H, brs), 6.54 (1H, d), 6.79 (1H,s).

[0627] LCMS: m/z 567 (M⁺+1).

[0628] (30d) In the same manner as in Example 3 (3c), the title compound(65 mg, 40%) was prepared as light yellow crystal powder from ethyl5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (175 mg) prepared in step (30c).

[0629]¹H-NMR (CDCl₃): δ 0.85 (3H, t), 1.09 (3H, t), 1.16-1.19 (6H, m),2.75-2.85 (1H, m), 3.38-3.66 (8H, m), 4.00 (3H, s), 4.04 (3H, s),4.88-4.93 (1H, m), 6.68 (1H, s), 6.70 (1H, d), 7.88 (1H, s), 9.31 (1H,s)

[0630] FABMS: m/z 521 (M⁺+1).

Example 31

[0631]7,8-Dimethoxy-2-(1-(2-(2-methoxyethoxy)ethoxycarbonyloxy)-2-methyloropyl)-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine

[0632] (31a) In the same manner as in Example 19 (19b), provided thatdiethylene glycol monomethyl ether (3.6 ml) was used instead of3-pentanol and trifluoroacetic acid (3.8 ml) was added, ethyl2-(1-(2-(2-methoxyethoxy)ethoxycarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(8.82 g, 5210) was prepared from ethyl2-(1-(1-imidazolylcarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(13.0 g) prepared in step (30a).

[0633]¹H-NMR (CDCl₃): δ 0.72 (3H, d), 1.07 (3H, d), 1.44 (3H, t),2.50-2.65 (1H, m), 3.36 (3H, s), 3.50-3.55 (2H, m), 3.60-3.65 (2H, m),3.65-3.75 (2H, m), 4.01 (3H, s), 4.04 (3H, s), 4.20-4.35 (2H, m), 4.49(2H, q), 6.35 (1H, d), 7.07 (1H, s), 7.62 (1H, s)

[0634] (31b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-4,5-dimethoxy)-2-(I-(2-(2-methoxyethoxy)ethoxycarbonyloxy)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (1.14 g,100%) was prepared from ethyl2-(1-(2-(2-methoxyethoxy)ethoxycarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(1.15 g) prepared in step (31a).

[0635]¹H-NMR (CDCl₃) δ 0.85 (3H, d), 1.15 (3H, d), 1.29 (3H, t),2.70-2.85 (1H, m), 3.36 (3H, s), 3.50-3.55 (2H, m), 3.60-3.65 (2H, m),3.64 (3H, s), 3.69-3.75 (2H, m), 3.90 (3H, s), 4.35 (2H, q), 4.20-4.40(2H, m), 6.14 (1H, s), 6.49 (2H, s), 6.53 (1H, d), 6.78 (1H, s).

[0636] (31c) In the same manner as in Example 3 (3c), the title compound(750 mg, 75%) was prepared as a light yellow crystal powder from ethyl5-(2-amino-4,5-dimethoxy)-2-(1-(2-(2-methoxyethoxy)ethoxycarbonyloxy)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (1.11mg) prepared in step (31b).

[0637]¹H-NMR (CDCl₃): δ 0.86 (3H, d), 1.17 (3H, d), 2.75-2.90 (1H, m),3.35 (3H, s), 3.50-3.55 (2H, m), 3.60-3.65 (2H, m), 3.71 (2H, t), 4.00(3H, s), 4.07 (3H, s), 4.26 (1H, dt), 4.34 (1H, dt), 6.68 (1H, d), 6.85(1H, s), 7.88 (iH, s), 9.94 (1H, s).

Example 32

[0638]2-(1-(1,3-Diethoxy-2-oropoxycarbonyloxy)-2-methylpropyl)-8-isopropoxy-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo [4,5-c][1]benzazepine

[0639] (32a) In the same manner as in Synthesis Example 2, ethyl5-(8-isopropoxy-4-methoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(1.47 g, 78%) was prepared from an about 1:1 mixture (2.49 g) of ethyl4-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-tri azole-5-carboxylate (Synthesis Example 3, b-1) and ethyl5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 3, b-2).

[0640]¹H-NMR (CDCl₃): δ 1.43 (9H, d), 4.00 (3H, s), 4.47 (2H, q),4.65-4.80 (1H, m), 7.00 (1H, s), 7.66 (1H, s).

[0641] (32b) p-Toluenesulfonic acid monohydrate (57 mg) and isobutylaldehyde (0.41 ml) were added to a solution of ethyl5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(1.14 g), prepared in step (32a), in methylene chloride solution (17 ml)at −20° C. The mixture was stirred at that temperature for one hr.1,1′-Carbonyldiimidazole (732 mg) was added to the reaction solution.Further, one hr after that, 1,3-diethoxy-2-propanol (4.70 ml) was addedthereto. The reaction solution was cooled to −30° C. Trifluoroaceticacid (0.70 ml) was added thereto. The temperature was raised to roomtemperature, followed by stirring for 25 hr. 0.5 M hydrochloric acid wasadded to the reaction solution under ice cooling to stop the reaction,and separation was then carried out. The organic layer was washed fivetimes with a 7% aqueous sodium hydrogencarbonate solution. The solventwas evaporated under reduced pressure. Diethyl ether and water wereadded to the residue. The organic layer after the separation wassuccessively washed twice with water, with 0.5 M hydrochloric acid,twice with water, and then with 20% saline. The solvent was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel (ethyl acetate/hexane) to give a crudeproduct of ethyl2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(1.15 g).

[0642]¹H-NMR (CDCl₃): δ 0.71 (3H, d), 1.07 (3H, d), 1.10 (3H, t), 1.15(3H, t), 1.41-1.47 (9H, m), 2.54-2.65 (1H, m), 3.40-3.64 (8H, m), 4.01(3H, s), 4.49 (2H, q), 4.68-4.76 (1H, m), 4.90-4.96 (1H, m), 6.39 (1H,d), 7.03 (1H, s), 7.61 (1H, s).

[0643] EIMS: m/z 624 (M⁺).

[0644] (32b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-5-isopropoxy-4-methoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate(1.08 g, 100%) was prepared from ethyl2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(1.12 g) prepared in step (32a).

[0645]¹H-NMR (CDCl₃): δ 0.85 (3H, d), 1.13 (3H, t), 1.18 (3H, t), 1.23(6H, 2d), 1.26 (3H, t), 1.49 (3H, d), 2.73-2.82 (1H, m), 3.40-3.68 (3H,m), 4.09-4.17 (1H, m), 4.33 (2H, q), 4.93-5.00 (1H, m), 6.13 (1H, s),6.46 (2H, s), 6.56 (1H, d), 6.83 (1H, s).

[0646] EIMS: m/z 594 (M⁺).

[0647] (32c) In the same manner as in Example 3 (3c), the title compound(634 mg, 65% in two steps) was prepared from ethyl5-(2-amino-5-isopropoxy-4-methoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate(1.08 g) prepared in step (32b).

[0648]¹H-NMR (CDCl₃): δ 0.85 (3H, d), 1.08 (3H, t), 1.17 (3H, d), 1.18(3H, t), 1.42 (6H, d), 2.78-2.90 (1H, m), 3.36-3.66 (8H, m), 4.03 (3H,s), 4.68-4.79 (1H, m), 4.90-5.00 (1H, m), 6.70 (1H, d), 6.79 (1H, s),7.90 (1H, s), 9.74 (1H, s).

[0649] EIMS: m/z 548 (M⁺).

Example 33

[0650]8-Isopropoxy-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzaz epine

[0651] (33a) Isobutyl aldehyde (2.9 ml), sodium iodide (3.18 g),potassium carbonate (11.69 g), and isopropyl chloroformate (7.2 ml) wereadded in that order under an argon atmosphere at room temperature to asolution of ethyl5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(8.01 g), prepared in step (32a), in acetone (150 ml). The mixture wasstirred at that temperature for 19.5 hr. Water was added to the reactionmixture to stop the reaction. The mixture was extracted with ethylacetate. The organic layer was washed with 20% saline and dried overanhydrous magnesium sulfate. The solvent was evaporated. The resultantmixture was purified by column chromatography on silica gel(hexane/ethyl acetate) to give ethyl2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(10.12 g, 89%).

[0652]¹H-NMR (CDCl₃): δ 0.72 (3H, d), 1.05 (3H, d), 1.26 (3H, d), 1.28(3H, d), 1.44 (3H, t), 2.57 (1H, m), 4.00 (3H, s), 4.49 (2H, q), 4.72(1H, m), 4.85 (1H, sept.) 6.36 (1H, d), 7.01 (1H, s), 7.60 (1H, s).

[0653] TSPMS: 537 (M⁺+1).

[0654] (33b) In the same manner as in Example 3 (3b), ethyl5-(2-amino-5-isopropoxy-4-methoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylatewas prepared from ethyl2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5-(5-isopropoxy-4-methoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate(10.12 g) prepared in step (33a).

[0655]¹H-NMR (CDCl₃): δ 0.85 (3H, d), 1.15 (3H, d), 1.22 (6H, d),1.2-1.4 (9H, m), 2.76 (1H, d), 3.87 (3H, s), 4.10 (1H, m), 4.30 (2H, m),4.88 (1H, sept.), 6.13 (1H, s), 6.53 (1H, d), 6.81 (1H, s)

[0656] TSPMS: 507 (M⁺+1).

[0657] (33c) A solution of ethyl5-(2-amino-5-isopropoxy-4-methoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate,prepared in step (33b), in acetic acid (100 ml) was stirred at 90° C.for 3.5 hr under an argon atmosphere. The reaction mixture wasconcentrated. Toluene was added to the concentrate, and the solution wasthen again concentrated. The concentrate was extracted with methylenechloride, followed by washing twice with a 7% aqueous sodiumhydrogencarbonate solution and once with 10% saline. The organic layerwas concentrated. The solvent was evaporated. The resultant mixture waswashed twice with isopropyl alcohol and purified by columnchromatography (chloroform/ethyl acetate) to give the title compound(4.02 g, 45% in two steps).

[0658]¹H-NMR (CDCl₃): δ 0.85 (3H, s), 1.16 (3H, d), 1.26 (3H, d), 1.31(3H, d), 1.42 (6H, d), 2.81 (1H, m), 4.03 (3H, s), 4.74 (1H, sept.),4.86 (1H, sept.), 6.68 (1H, d), 6.76 (1H, s), 7.90 (1H, s), 9.64 (1H,brs)

[0659] FABMS: 461 (M⁺+1).

[0660] The title compounds of Examples 1 to 33 have the followingrespective chemical formulae. TABLE 1

Example R³¹ (or R³²) R³² (or R³¹) Q 1 H CH₃ OCO₂CH(CH₃)₂ 2 H HOCOC(CH₃)₃

[0661] TABLE 2

Ex- am- ple R⁴² R³¹ (orR³²) R³² (orR³¹) R³³  3 OCH₃ H H CH₂CH₃  4 OCH₃ HH CH₂CH(CH₃)₂  5 OCH₃ H H (CH₂)₅CH₃  6 OCH₃ H H (CH₂)₃CH₃  7 OCH₃ H HCH(CH₃)₂ 17a OCH₃ H H C₆H₄NO₂-p 19 OCH₃ H CH₂CH₃ CH(CH₂CH₃)₂ 20 OCH₃ HCH(CH₃)₂ CH(CH₃)₂ 30 OCH₃ H CH(CH₃)₂ CH(CH₂OCH₂CH₃)₂ 31 OCH₃ H CH(CH₃)₂(CH₂CH₂O)₂CH₃ 32 OCH(CH₃)₂ H CH(CH₃)₂ CH(CH₂OCH₂CH₃)₂ 33 OCH(CH₃)₂ HCH(CH₃)₂ CH(CH₃)₂

[0662] TABLE 3

Example R³¹ (R³²) R³² (R³¹) R³⁴  8 H H C₆H₅  9 H H (CH₂)₁₀CH₃ 10 H H(CH₂)₁₄CH₃ 11 H H (CH₂)₃Cl 12 H H C₆H₄NH₂-p 13 H H

14 H H

15 H CH₃ CH(CH₃)₂ 16 H H CH₂C₆H₄OCH₃-p 21 H H CH₃ 22 H H CH(CH₃)₂ 23 H H(CH₂)₂CH₃ 24 H H (CH₂)₂CO₂H 25 H H

[0663] TABLE 4

Example R³¹ (R³²) R³² (R³¹) Q 13c H H Cl 15c H CH₃ Cl 17 H HOCONH((CH₂)₂N(CH₃)₂) 18 H H OPO(OCH₂CH₃)₂ 26 CH₂CH₃ CH₂CH₃ OCH₃ 27(CH₂)₂CH₃ (CH₂)₂CH₃ OCH₂CH₃ 28 H H OCH₂CH₃ 29 H H OCH(CH₃)₂

Preparation Example 1 Preparation of Tablet

[0664] The compound of Example 20 (50.0 g), lactose (139.0 g),hydroxypropylcellulose (HPC-SL: 6.0 g), calcium carmellose (4.0 g), andpurified water (9.0 g) were intimately mixed with one another. Themixture was granulated, dried, and subjected to granule size regulation.Magnesium stearate (1.0 g) was added to and intimately mixed with thegranule, followed by tabletting to prepare tablets containing 50 mg ofthe compound, prepared in Example 20, per tablet.

Preparation Example 2 Preparation of Subtilized Granule

[0665] The compound of Example 20 (50.0 g), lactose (420 g),hydroxypropylcellulose (HPC-SL: 15 g), calcium carmellose (10 g), andpurified water (30 g) were intimately mixed with one another. Themixture was granulated, dried, subjected to granule size regulation, andscreened. Magnesium stearate (5.0 g) was added to and intimately mixedtherewith to prepare subtilized granules containing 100 mg of thecompound of Example 20 per g of the preparation.

Pharmacological Test Example

[0666] The compound of Synthesis Example 1, the compound of Example 7,and the compound of Example 20 were suspended or dissolved in a 0.5%aqueous methylcellulose solution. The resultant solutions were orallyadministered in an equimolar amount to dogs and rats. After theadministration, the amount of each compound contained in plasma of eachanimal individual was quantitatively determined by HPLC. The resultswere as summarized in Table 5. The absorption in each specimen wasassayed by the area under a medicament level of plasma vs time curve(AUC). As a result, AUCs obtained by the compounds of Examples 7 and 20as prodrugs were 3 to 4 times higher for the dog and 3 to 7 times higherfor the rat compared with the compound of Synthesis Example 1 as anactivator body. TABLE 5 AUC Compound Dog (μmol · hr/L) Rat (μmol · hr/L)Synthesis 0.3 ± 0.1 0.2 ± 0.1 Example 1 Example 7 0.9 ± 0.1 0.6 ± 0.1Example 20 1.2 ± 0.3 1.4 ± 0.1

[0667] Acute Toxicity Test by Single Administration

[0668] The compound of Example 20 was homogeneously suspended in a 0.5%aqueous methylcellulose solution. The suspension was forcibly orallyadministered to ICR male mice (5 weeks old). As a result, all the micesurvived and developed no abnormality at a dose of 2 g/kg of thecompound of Example 20.

1. A compound represented by formula (I) or a physiologically acceptablesalt or solvate thereof:

wherein R¹ represents a hydrogen atom, a hydroxyl group, C₁₋₄ alkyl, orphenyl C₁₋₄ alkyl; R², R³, R⁴, and R⁵, which may be the same ordifferent, represent any one of the following (a) to (n): (a) a hydrogenatom; (b) a halogen atom; (c) an optionally protected hydroxyl group;(d) formyl; (e) C₁₋₁₂ alkyl which may be substituted by a halogen atom;(f) C₁₋₁₂ alkenyl which has one or more carbon-carbon double bonds andmay be substituted by (1) a halogen atom, (2) cyano, (3) —COR⁹ whereinR⁹ represents a hydrogen atom or C₁₋₆ alkyl, (4) —COOR¹⁰ wherein R¹⁰represents a hydrogen atom or C₁₋₆ alkyl, (5) —CONR¹¹R¹² wherein R¹¹ andR¹², which may be the same or different, represent (i) a hydrogen atom,(ii) C₁₋₆ alkyl which may be substituted by amino optionally substitutedby C₁₋₄ alkyl, phenyl optionally substituted by C₁₋₄ alkyl which may besubstituted by a saturated five- to seven-membered heterocyclic ringcontaining one or two nitrogen atoms (the nitrogen atoms may besubstituted by C₁₋₄ alkyl), or a saturated or unsaturated five- toseven-membered heterocyclic ring, (iii) phenyl which may be substitutedby carboxyl, or (iv) a saturated or unsaturated five to seven-memberedheterocyclic ring, (6) a saturated or unsaturated five- toseven-membered heterocyclic ring which may be substituted by C₁₋₄ alkylor may form a bicyclic ring fused with another ring; (g) C₁₋₁₂ alkoxywhich may be substituted by (1) a halogen atom, (2) a hydroxyl group,(3) cyano, (4) C₃₋₇ cycloalkyl, (5) phenyl, (6) C₁₋₄ alkoxy, (7)phenoxy, (8) amino which may be substituted by C₁₋₄ alkyl, (9) —COR¹³wherein R¹³ represents a hydrogen atom, C₁₋₆ alkyl, phenyl optionallysubstituted by halogen or C₁₋₄ alkoxy, or phenyl C₁₋₄ alkyl, (10)—COOR¹⁴ wherein R¹⁴ represents a hydrogen atom or C₁₋₆ alkyl, (11)—CONR¹⁵R¹⁶ wherein R₁₅ and R¹⁶, which may be the same or different,represent a hydrogen atom or C₁₋₆ alkyl which may be substituted by asaturated or unsaturated five- to seven-membered heterocyclic ring, or(12) a saturated or unsaturated five- to seven-membered heterocyclicring which may be substituted by C₁₋₄ alkyl or phenyl C₁₋₄ alkyl; (h)—C═N—OR¹⁶ wherein R¹⁰ represents a hydrogen atom, C₁₋₆ alkyl, phenylC₁₋₄ alkyl, or phenyl; (i) —(CH₂)mOR¹⁷ wherein m is an integer of 0 to4, and R¹⁷ represents a hydrogen atom, C₁₋₆ alkyl, or phenyl C₁₋₄ alkylof which one or more hydrogen atoms on the benzene ring may besubstituted by C₁₋₄ alkyl; (j) —(CH₂)k—COR¹⁸ wherein k is an integer of1 to 4, and R¹⁸ represents a hydrogen atom or C₁₋₄ alkyl; (k)—(CH₂)j—COOR¹⁹ wherein j is an integer of 0 to 4, and R¹⁹ represents ahydrogen atom or C₁₋₆ alkyl; (l) —(CH₂)p—NR²⁰R²¹ wherein p is an integerof 1 to 4, and R²⁰ and R²¹, which may be the same or different,represent (1) a hydrogen atom, (2) C₁₋₆ alkyl which may be substitutedby amino optionally substituted by C₁₋₄ alkyl, (3) phenyl C₁₋₄ alkyl,(4) —COR²² wherein R²² represents a hydrogen atom or C₁₋₄ alkyl whichmay be substituted by carboxyl, or (5) —SO₂R²³ wherein R²³ representsC₁₋₄ alkyl or phenyl which may be substituted by a halogen atom; (m)—(CH₂)q—CONR²⁴R²⁵ wherein q is an integer of 0 to 4, and R²⁴ and R²⁵,which may be the same or different, represent a hydrogen atom, asaturated or unsaturated five- to seven-membered heterocyclic ring, orC₁₋₆ alkyl which may be substituted by a saturated or unsaturated five-to seven-membered heterocyclic ring, or alternatively R²⁴ and R²⁵ mayform a saturated or unsaturated five- to seven-membered heterocyclicring together with a nitrogen atom to which they are attached (theheterocyclic ring may further contain at least one oxygen, nitrogen, orsulfur atom, may form a bicyclic ring fused with another ring, or may besubstituted by C₁₋₄ alkyl); and (n) —NR²⁶R²⁷ wherein R²⁶ and R²⁷, whichmay be the same or different, represent a hydrogen atom or —COR²⁸wherein R²⁸ represents a hydrogen atom, C₁₋₆ alkyl, or phenyl which maybe substituted by C₁₋₄ alkyl or C₁₋₆ alkoxy optionally substituted byphenyl; R³¹ and R³², which may be the same or different, represent ahydrogen atom or C₁₋₆ alkyl which may be substituted by a halogen atom;and Q represents a group selected from the following groups (i) to (iv)or a halogen atom or C₁₋₆ alkoxy:

wherein R³³ represents C₁₋₆ alkyl which may be substituted by C₁₋₆alkoxy optionally substituted by C₁₋₆ alkoxy, phenyl optionallysubstituted by C₁₋₆ alkoxy, amino, or nitro, or a saturated orunsaturated five- to seven-membered heterocyclic ring optionallysubstituted by C₁₋₆ alkoxy, amino, or nitro, phenyl which may besubstituted by C₁₋₆ alkoxy, amino, or nitro, or a saturated orunsaturated five- to seven-membered heterocyclic ring which may besubstituted by C₁₋₆ alkoxy, amino, or nitro, or R³ may form C₁₋₄alkylene together with R¹ or R², R³⁴ represents C₁₋₁₆alkyl which may besubstituted by a halogen atom, carboxyl, phenyl optionally substitutedby C₁₋₆ alkoxy, amino, or nitro, or a saturated or unsaturated five- toseven-membered heterocyclic ring optionally substituted by C₁₋₆ alkoxy,amino, or nitro, phenyl which may be substituted by C₁₋₆ alkoxy, amino,or nitro, or a saturated or unsaturated five- to seven-memberedheterocyclic ring which may be substituted by C₁₋₆ alkoxy, amino, ornitro, R³⁵ and R³⁶, which may be the same or different, represent ahydrogen atom or C₁₋₆ alkyl which may be substituted by amino optionallysubstituted by C₁₋₄ alkyl or R³⁵ and R³⁶ may form a saturated orunsaturated five- to seven-membered heterocyclic ring together with anitrogen atom to which they are attached, and R³⁷ and R³⁸, which may bethe same or different, represent C₁₋₆ alkyl.
 2. A compound according toclaim 1, wherein R¹ represents a hydrogen atom and R², R³, R⁴, and R⁵represent a hydrogen atom or (g) C₁₋₁₂ alkoxy.
 3. A compound accordingto claim 1, wherein R¹, R², and R⁵ represent a hydrogen atom and R³ andR⁴ represent a hydrogen atom or (g) C₁₋₁₂ alkoxy.
 4. A compoundaccording to claim 1, wherein R¹, R², R⁴, and R⁵ represent a hydrogenatom and R³ represents (g) C₁₋₁₂ alkoxy.
 5. A compound according toclaim 1, wherein R¹, R², R³, and R⁵ represent a hydrogen atom and R⁴represents (g) C₁₋₁₂ alkoxy.
 6. A compound represented by formula (Ia)or a pharmacologically acceptable salt or solvate thereof:

wherein R⁴¹ and R⁴², which may be the same or different, represent ahydrogen atom, optionally protected hydroxyl, C₁₋₆ alkoxy which may besubstituted by a halogen atom, or C₁₋₆ alkyl which may be substituted bya halogen atom and R³¹, R³², and Q are as defined in claim
 1. 7. Acompound according to claim 6, wherein R⁴¹ and R⁴² represent C₁₋₁₆alkoxy and Q represents group (i). 8.2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine,2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine,2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-8-isopropoxy-7-methoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine, or8-isopropoxy-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7-methoxy-4(5H), 10-dioxo-2H-1, 2, 3-triazolo[4,5-c][1]benzazepine, or a salt or solvate thereof.
 9. Apharmaceutical composition comprising the compound according to any oneof claims 1 to 8 or a pharmacologically acceptable salt or solvatethereof.
 10. A pharmaceutical composition according to claim 9 for usein the treatment of allergic diseases.
 11. A method for the treatment ofan allergic disease, comprising administering to mammals the compoundaccording to any one of claims 1 to 8 or a pharmacologically acceptablesalt or solvate thereof together with a pharmaceutically acceptablecarrier.
 12. Use of the compound according to any one of claims 1 to 8or a pharmacologically acceptable salt or solvate thereof for preparinga therapeutic agent for allergic diseases.
 13. A compound represented byformula (II) or a salt or solvate thereof:

wherein R⁵¹ represents nitro or amino, R⁵² represents a hydrogen atom ora protective group for carboxyl, and Q, R² to R⁵, R³¹, and R³² are asdefined in claim
 1. 14. A compound represented by formula (II′) or asalt or solvate thereof:

wherein Q, R² to R⁵, R³¹, R³², R⁵¹, and R⁵² are as defined in claims 1and
 13. 15. A compound represented by formula (VI) or a salt or solvatethereof:

wherein Q, R² to R⁵, R³¹, R³², and R⁵² are as defined in claims 1 and13.
 16. A compound represented by formula (VI′) or a salt or solvatethereof:

wherein Q, R² to R⁵, R³¹, and R³² are as defined in claims 1 and
 13. 17.A compound represented by formula (VII) or a salt or solvate thereof:

wherein R² to R⁵ and R⁵² are as defined in claims 1 and
 13. 18. Acompound represented by formula (VIII) or a salt or solvate thereof:

wherein R⁶¹ represents a protective group for triazole and R² to R⁵ andR⁵² are as defined in claims 1 and
 13. 19. A process for preparing acompound represented by formula (IIa′)

wherein Q represents group (i) as defined in claim 1 and R² to R⁵, R³¹,R³², and R⁵² are as defined in claims 1 and 13, which comprises thesteps of: (1) reacting a compound represented by formula (V)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, with acompound represented by R³¹R³²C═O wherein R³¹ and R³² are as definedabove in claim 1; (2) reacting the compound prepared in step (1) with acompound represented by R⁷¹—C(═O)—R⁷² wherein R⁷¹ and R⁷² eachindependently represent a chlorine atom, 4-nitrophenyl, or 1-imidazolyl;and (3) reacting the compound prepared in step (2) with a compoundrepresented by R³³OH wherein R³³ is as defined in claim
 1. 20. A processfor preparing a compound represented by formula (IIa′)

wherein Q represents the group (i) as defined in claim 1 and R² to R⁵,R³¹, R³², and R⁵² are as defined in claims 1 and 13, which comprises thesteps of: (1) reacting a compound represented by formula (V)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, with acompound represented by R³¹R³²C═O wherein R³¹ and R³² are as defined inclaim 1; and (2) reacting the compound prepared in step (1) with acompound represented by HalCOOR³³ wherein Hal represents a halogen atomand R³³ is as defined in claim 1, in the presence of an alkali metalcarbonate and an alkali metal iodide.
 21. A process for preparing acompound represented by formula (IIa′)

wherein Q represents group (i) as defined in claim 1 and R² to R⁵, R³¹,R³², and R⁵² are as defined in claims 1 and 13, which comprises the stepof reacting a compound represented by formula (V)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, with acompound represented by formula (IV)

wherein Hal represents a halogen atom, Q represents the group (i) asdefined in claim 1, and R³¹ and R³² are as defined above, in thepresence of an inorganic base and an alkali metal iodide.
 22. A processfor producing a compound represented by formula (VI′)

wherein Q represents the group (i) as defined in claim 1, R² to R⁵, R³¹,R³², and R⁵² are defined in claims 1 and 13, which comprises the stepsof: (1) reacting a compound represented by formula (VII)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, with acompound represented by R³¹R³²C═O wherein R³¹ and R³² are as defined inclaim 1; (2) reacting the compound prepared in step (1) with a compoundrepresented by R⁷¹—C(═O)—R⁷² wherein R⁷¹ and R⁷² each independentlyrepresent a chlorine atom, 4-nitrophenyl, or 1-imidazolyl; and (3)reacting the compound prepared in step (2) with a compound representedby R³³OH wherein R³³ is as defined in claim
 1. 23. A process forpreparing a compound represented by formula (VI′)

wherein Q represents group (i) as defined in claim 1, R² to R⁵, R³¹,R³², and R⁵² are as defined in claims 1 and 13, which comprises thesteps of: (1) reacting a compound represented by formula (VII)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, with acompound represented by R³¹R³²C═O wherein R³¹ and R³² are as defined inclaim 1; and (2) reacting the compound prepared in step (1) with acompound represented by HalCOOR³³ wherein Hal represents a halogen atomand R³³ is as defined in claim 1, in the presence of an alkali metalcarbonate and an alkali metal iodide.
 24. A process for producing acompound represented by formula (VI′)

wherein Q represents group (i) as defined in claim 1, R² to R⁵, R³¹,R³², and R⁵² are as defined in claims 1 and 13, which comprises the stepof reacting a compound represented by formula (VII)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, with acompound represented by formula (IV)

wherein Hal represents a halogen atom, Q represents the group (i) asdefined in claim 1, and R³¹ and R³² are as defined above, in thepresence of an inorganic base and an alkali metal iodide.
 25. A processfor preparing a compound represented by formula (VIII)

wherein R² to R⁵, R⁵², and R⁶¹ are as defined in claims 1, 13, and 18,which comprises the step of (a) reacting a compound represented byformula (IX)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, with acompound represented by formula (X) R⁶¹—N₃  (X) wherein R⁶¹ is asdefined in claim 18, or (b) reacting a compound represented by formula(XII)

wherein M represents lithium, magnesium chloride, magnesium bromide,magnesium iodide, zinc bromide, zinc iodide, cadmium bromide, iodidecadmium, or copper and R² to R⁵ are as defined in claim 1, with acompound represented by formula (XIII)

wherein R⁵² and R⁶¹ are as defined in claims 13 and
 18. 26. A processaccording to claim 25, which further comprises the step of, prior to thereaction of the compound represented by formula (IX) with the compoundrepresented by formula (X) in step (a), dehydrogenating a compoundrepresented by formula (XI)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, to producethe compound represented by formula (IX).
 27. A process for producing acompound represented by formula (XV)

wherein R² to R⁵, R⁵², and R⁶¹ are as defined in claims 1, 13 and 18,which comprises the step of reacting a compound represented by formula(XVI)

wherein R² to R⁵, and R⁵² are as defined in claims 1 and 13, with acompound represented by formula (X) R⁶¹—N₃  (X) wherein R⁶¹ is asdefined in claim
 18. 28. A process according to claim 27, which furthercomprises the step of, prior to the reaction of the compound representedby formula (XVI) with the compound represented by formula (X), acompound represented by formula (XVII)

wherein R² to R⁵ and R⁵² are as defined in claims 1 and 13, isdehydrogenated to produce the compound represented by formula (XVI). 29.A compound represented by formula (IXa) or a salt or solvate thereof

wherein R⁴¹, R⁴², and R⁵² are as defined above in claims 6 and 13,provided that R⁴¹ and/or R⁴² do not represent a hydrogen atom.
 30. Acompound represented by formula (XVIa) or a salt or solvate thereof

wherein R⁴¹, R⁴², R₅₁, and R⁵² are as defined in claims 6 and 13.